Mosquitoes sense infrared from body heat to help track humans down

While a mosquito bite is often no more than a temporary bother, in many parts of the world it can be scary. One mosquito species, Aedes aegypti, spreads the viruses that cause over 100,000,000 cases of dengue, yellow fever, Zika and other diseases every year. Another, Anopheles gambiae, spreads the parasite that causes malaria. The World Health Organization estimates that malaria alone causes more than 400,000 deaths every year. Indeed, their capacity to transmit disease has earned mosquitoes the title of deadliest animal.

Male mosquitoes are harmless, but females need blood for egg development. It's no surprise that there's over 100 years of rigorous research on how they find their hosts. Over that time, scientists have discovered there is no one single cue that these insects rely on. Instead, they integrate information from many different senses across various distances.

A team led by researchers at UC Santa Barbara has added another sense to the mosquito's documented repertoire: infrared detection. Infrared radiation from a source roughly the temperature of human skin doubled the insects' overall host-seeking behavior when combined with CO2 and human odor. The mosquitoes overwhelmingly navigated toward this infrared source while host seeking. The researchers also discovered where this infrared detector is located and how it works on a morphological and biochemical level. The results are detailed in the journalNature.

"The mosquito we study, Aedes aegypti, is exceptionally skilled at finding human hosts," said co-lead author Nicolas DeBeaubien, a former graduate student and postdoctoral researcher at UCSB in Professor Craig Montell's laboratory. "This work sheds new light on how they achieve this."

Guided by thermal infrared

It is well established that mosquitoes like Aedes aegypti use multiple cues to home in on hosts from a distance. "These include CO2 from our exhaled breath, odors, vision, [convection] heat from our skin, and humidity from our bodies," explained co-lead author Avinash Chandel, a current postdoc at UCSB in Montell's group. "However, each of these cues have limitations." The insects have poor vision, and a strong wind or rapid movement of the human host can throw off their tracking of the chemical senses. So the authors wondered if mosquitoes could detect a more reliable directional cue, like infrared radiation.

Within about 10 cm, these insects can detect the heat rising from our skin. And they can directly sense the temperature of our skin once they land. These two senses correspond to two of the three kinds of heat transfer: convection, heat carried away by a medium like air, and conduction, heat via direct touch. But energy from heat can also travel longer distances when converted into electromagnetic waves, generally in the infrared (IR) range of the spectrum. The IR can then heat whatever it hits. Animals like pit vipers can sense thermal IR from warm prey, and the team wondered whether mosquitoes, like Aedes aegypti, could as well.

The researchers put female mosquitoes in a cage and measured their host-seeking activity in two zones. Each zone was exposed to human odors and CO2 at the same concentration that we exhale. However, only one zone was also exposed to IR from a source at skin temperature. A barrier separated the source from the chamber prevented heat exchange through conduction and convection. They then counted how many mosquitoes began probing as if they were searching for a vein.

Adding thermal IR from a 34º Celcius source (about skin temperature) doubled the insects' host-seeking activity. This makes infrared radiation a newly documented sense that mosquitoes use to locate us. And the team discovered it remains effective up to about 70 cm (2.5 feet).

"What struck me most about this work was just how strong of a cue IR ended up being," DeBeaubien said. "Once we got all the parameters just right, the results were undeniably clear."

Previous studies didn't observe any effect of thermal infrared on mosquito behavior, but senior author Craig Montell suspects this comes down to methodology. An assiduous scientist might try to isolate the effect of thermal IR on insects by only presenting an infrared signal without any other cues. "But any single cue alone doesn't stimulate host-seeking activity. It's only in the context of other cues, such as elevated CO2 and human odor that IR makes a difference," said Montell, the Duggan and Distinguished Professor of Molecular, Cellular, and Developmental Biology. In fact, his team found the same thing in tests with only IR: infrared alone has no impact.

A trick for sensing infrared

It isn't possible for mosquitoes to detect thermal infrared radiation the same way they would detect visible light. The energy of IR is far too low to activate the rhodopsin proteins that detect visible light in animal eyes. Electromagnetic radiation with a wavelength longer than about 700 nanometers won't activate rhodopsin, and IR generated from body heat is around 9,300 nm. In fact, no known protein is activated by radiation with such long wavelengths, Montell said. But there is another way to detect IR.

Consider heat emitted by the sun. The heat is converted into IR, which streams through empty space. When the IR reaches Earth, it hits atoms in the atmosphere, transferring energy and warming the planet. "You have heat converted into electromagnetic waves, which is being converted back into heat," Montell said. He noted that the IR coming from the sun has a different wavelength from the IR generated by our body heat, since the wavelength depends on the temperature of the source.

The authors thought that perhaps our body heat, which generates IR, might then hit certain neurons in the mosquito, activating them by heating them up. That would enable the mosquitoes to detect the radiation indirectly.

Scientists have known that the tips of a mosquito's antennae have heat-sensing neurons. And the team discovered that removing these tips eliminated the mosquitoes' ability to detect IR.

Indeed, another lab found the temperature-sensitive protein, TRPA1, in the end of the antenna. And the UCSB team observed that animals without a functional trpA1 gene, which codes for the protein, couldn't detect IR.

The tip of each antenna has peg-in-pit structures that are well adapted to sensing radiation. The pit shields the peg from conductive and convective heat, enabling the highly directional IR radiation to enter and warm up the structure. The mosquito then uses TRPA1 -- essentially a temperature sensor -- to detect infrared radiation.

Diving into the biochemistry

The activity of the heat-activated TRPA1 channel alone might not fully explain the range over which mosquitoes were able to detect IR. A sensor that exclusively relied on this protein may not be useful at the 70 cm range the team had observed. At this distance there likely isn't sufficient IR collected by the peg-in-pit structure to heat it enough to activate TRPA1.

Fortunately, Montell's group thought there might be more sensitive temperature receptors based on their previous work on fruit flies in 2011. They had found a few proteins in the rhodopsin family that were quite sensitive to small increases in temperature. Although rhodopsins were originally thought of exclusively as light detectors, Montell's group found that certain rhodopsins can be triggered by a variety of stimuli. They discovered that proteins in this group are quite versatile, involved not just in vision, but also in taste and temperature sensing. Upon further investigation, the researchers discovered that two of the 10 rhodopsins found in mosquitoes are expressed in the same antennal neurons as TRPA1.

Knocking out TRPA1 eliminated the mosquito's sensitivity to IR. But insects with faults in either of the rhodopsins, Op1 or Op2, were unaffected. Even knocking out both the rhodopsins together didn't entirely eliminate the animal's sensitivity to IR, although it significantly weakened the sense.

Their results indicated that more intense thermal IR -- like what a mosquito would experience at closer range (for example, around 1 foot) -- directly activates TRPA1. Meanwhile, Op1 and Op2 can get activated at lower levels of thermal IR, and then indirectly trigger TRPA1. Since our skin temperature is constant, extending the sensitivity of TRPA1 effectively extends the range of the mosquito's IR sensor to around 2.5 ft.

A tactical advantage

Half the world's population is at risk for mosquito-borne diseases, and about a billion people get infected every year, Chandel said. What's more, climate change and worldwide travel have extended the ranges of Aedes aegypti beyond tropical and subtropical countries. These mosquitoes are now present in places in the US where they were never found just a few years ago, including California.

The team's discovery could provide a way to improve methods for suppressing mosquito populations. For instance, incorporating thermal IR from sources around skin temperature could make mosquito traps more effective. The findings also help explain why loose-fitting clothing is particularly good at preventing bites. Not only does it block the mosquito from reaching our skin, it also allows the IR to dissipate between our skin and the clothing so the mosquitoes cannot detect it.

"Despite their diminutive size, mosquitoes are responsible for more human deaths than any other animal," DeBeaubien said. "Our research enhances the understanding of how mosquitoes target humans and offers new possibilities for controlling the transmission of mosquito-borne diseases."

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Mitochondria are flinging their DNA into our brain cells

As direct descendants of ancient bacteria, mitochondria have always been a little alien.

Now a study shows that mitochondria are possibly even stranger than we thought.

Mitochondria in our brain cells frequently fling their DNA into the nucleus, the study found, where the DNA becomes integrated into the cells' chromosomes. And these insertions may be causing harm: Among the study's nearly 1,200 participants, those with more mitochondrial DNA insertions in their brain cells were more likely to die earlier than those with fewer insertions.

"We used to think that the transfer of DNA from mitochondria to the human genome was a rare occurrence," says Martin Picard, mitochondrial psychobiologist and associate professor of behavioral medicine at Columbia University Vagelos College of Physicians and Surgeons and in the Robert N. Butler Columbia Aging Center. Picard led the study with Ryan Mills of the University of Michigan.

"It's stunning that it appears to be happening several times during a person's lifetime, Picard adds. "We found lots of these insertions across different brain regions, but not in blood cells, explaining why dozens of earlier studies analyzing blood DNA missed this phenomenon."

Mitochondrial DNA behaves like a virus

Mitochondria live inside all our cells, but unlike other organelles, mitochondria have their own DNA, a small circular strand with about three dozen genes. Mitochondrial DNA is a remnant from the organelle's forebears: ancient bacteria that settled inside our single-celled ancestors about 1.5 billion years ago.

In the past few decades, researchers discovered that mitochondrial DNA has occasionally "jumped" out of the organelle and into human chromosomes.

"The mitochondrial DNA behaves similar to a virus in that it makes use of cuts in the genome and pastes itself in, or like jumping genes known as retrotransposons that move around the human genome," says Mills.

The insertions are called nuclear-mitochondrial segments -- NUMTs ("pronounced new-mites") -- and have been accumulating in our chromosomes for millions of years.

"As a result, all of us are walking around with hundreds of vestigial, mostly benign, mitochondrial DNA segments in our chromosomes that we inherited from our ancestors," Mills says.

Mitochondrial DNA insertions are common in the human brain

Research in just the past few years has shown that "NUMTogenesis" is still happening today.

"Jumping mitochondrial DNA is not something that only happened in the distant past," says Kalpita Karan, a postdoc in the Picard lab who conducted the research with Weichen Zhou, a research investigator in the Mills lab. "It's rare, but a new NUMT becomes integrated into the human genome about once in every 4,000 births. This is one of many ways, conserved from yeast to humans, by which mitochondria talk to nuclear genes."

The realization that new inherited NUMTs are still being created made Picard and Mills wonder if NUMTs could also arise in brain cells during our lifespan.

"Inherited NUMTs are mostly benign, probably because they arise early in development and the harmful ones are weeded out," says Zhou. But if a piece of mitochondrial DNA inserts itself within a gene or regulatory region, it could have important consequences on that person's health or lifespan. Neurons may be particularly susceptible to damage caused by NUMTs because when a neuron is damaged, the brain does not usually make a new brain cell to take its place.

To examine the extent and impact of new NUMTs in the brain, the team worked with Hans Klein, assistant professor in the Center for Translational and Computational Neuroimmunology at Columbia, who had access to DNA sequences from participants in the ROSMAP aging study (led by David Bennett at Rush University). The researchers looked for NUMTs in different regions of the brain using banked tissue samples from more than 1,000 older adults.

Their analysis showed that nuclear mitochondrial DNA insertion happens in the human brain -- mostly in the prefrontal cortex -- and likely several times over during a person's lifespan.

They also found that people with more NUMTs in their prefrontal cortex died earlier than individuals with fewer NUMTs. "This suggests for the first time that NUMTs may have functional consequences and possibly influence lifespan," Picard says. "NUMT accumulation can be added to the list of genome instability mechanisms that may contribute to aging, functional decline, and lifespan."

Stress accelerates NUMTogenesis

What causes NUMTs in the brain, and why do some regions accumulate more than others?

To get some clues, the researchers looked at a population of human skin cells that can be cultured and aged in a dish over several months, enabling exceptional longitudinal "lifespan" studies.

These cultured cells gradually accumulated several NUMTs per month, and when the cells' mitochondria were dysfunctional from stress, the cells accumulated NUMTs four to five times more rapidly.

"This shows a new way by which stress can affect the biology of our cells," Karan says. "Stress makes mitochondria more likely to release pieces of their DNA and these pieces can then 'infect' the nuclear genome," Zhou adds. It's just one way mitochondria shape our health beyond energy production.

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New insights on how bird flu crosses the species barrier

In recent years, public health measures, surveillance, and vaccination have helped bring about significant progress in reducing the impact of seasonal flu epidemics, caused by human influenza viruses A and B. However, a possible outbreak of avian influenza A (commonly known as 'bird flu') in mammals, including humans, poses a significant threat to public health.

The Cusack group at EMBL Grenoble studies the replication process of influenza viruses. A new study from this group sheds light on the different mutations that the avian influenza virus can undergo to be able to replicate in mammalian cells.

Some avian influenza strains can cause severe disease and mortality. Fortunately, significant biological differences between birds and mammals normally prevent avian influenza from spreading from birds to other species. To infect mammals, the avian influenza virus must mutate to overcome two main barriers: the ability to enter the cell and to replicate within that cell. To cause an epidemic or pandemic, it must also acquire the ability to be transmitted between humans.

However, sporadic contamination of wild and domestic mammals by bird flu is becoming increasingly common. Of particular concern is the recent unexpected infection of dairy cows in the USA by an avian H5N1 strain, which risks becoming endemic in cattle. This might facilitate adaptation to humans, and indeed, a few cases of transmission to humans have been reported, so far resulting in only mild symptoms.

At the heart of this process is the polymerase, an enzyme that orchestrates the virus's replication inside host cells. This flexible protein can rearrange itself according to the different functions it performs during infection. These include transcription -- copying the viral RNA into messenger RNA to make viral proteins -- and replication -- making copies of the viral RNA to package into new viruses.

Viral replication is a complex process to study because it involves two viral polymerases and a host cell protein -- ANP32. Together, these three proteins form the replication complex, a molecular machine that carries out replication. ANP32 is known as a 'chaperone', meaning that it acts as a stabiliser for certain cellular proteins. It can do this thanks to a key structure -- its long acidic tail. In 2015, it was discovered that ANP32 is critical for influenza virus replication, but its function was not fully understood.

The results of the new study, published in the journal Nature Communications, show that ANP32 acts as a bridge between the two viral polymerases -- called replicase and encapsidase. The names reflect the two distinct conformations taken up by the polymerases to perform two different functions -- creating copies of the viral RNA (replicase) and packaging the copy inside a protective coating with ANP32's help (encapsidase).

Through its tail, ANP32 acts as a stabiliser for the replication complex, allowing it to form within the host cell. Interestingly, the ANP32 tail differs between birds and mammals, although the core of the protein remains very similar. This biological difference explains why the avian influenza virus does not replicate easily in mammals and humans.

"The key difference between avian and human ANP32 is a 33-amino-acid insertion in the avian tail, and the polymerase has to adapt to this difference," explained Benoît Arragain, a postdoctoral fellow in the Cusack group and first author of the publication. "For the avian-adapted polymerase to replicate in human cells, it must acquire certain mutations to be able to use human ANP32."

To better understand this process, Arragain and his collaborators obtained the structure of the replicase and encapsidase conformations of a human-adapted avian influenza polymerase (from strain H7N9) while they were interacting with human ANP32. This structure gives detailed information about which amino acids are important in forming the replication complex and which mutations could allow the avian influenza polymerase to adapt to mammalian cells.

To obtain these results, Arragain carried out in vitro experiments at EMBL Grenoble, using the Eukaryotic Expression Facility, the ISBG biophysical platform, and the cryo-electron microscopy platform available through the Partnership for Structural Biology. "We also collaborated with the Naffakh group at the Institut Pasteur, who carried out cellularexperiments," added Arragain. "In addition, we obtained the structure of the human type B influenza replication complex, which is similar to that of influenza A. The cellular experiments confirmed our structural data."

These new insights into the influenza replication complex can be used to study polymerase mutations in other similar strains of the avian influenza virus. It is therefore possible to use the structure obtained from the H7N9 strain and adapt it to other strains such as H5N1.

"The threat of a new pandemic caused by highly pathogenic, human-adapted avian influenza strains with a high mortality rate needs to be taken seriously," said Stephen Cusack, EMBL Grenoble Senior Scientist who led the study and has been studying influenza viruses for 30 years. "One of the key responses to this threat includes monitoring mutations in the virus in the field. Knowing this structure allows us to interpret these mutations and assess if a strain is on the path of adaptation to infect and transmit between mammals."

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What shapes a virus's pandemic potential? SARS-CoV-2 relatives yield clues

Two of the closest known relatives to SARS-CoV-2 -- a pair of bat coronaviruses discovered by researchers in Laos -- may transmit poorly in people despite being genetically similar to the COVID-19-causing virus, a new Yale study reveals.

The findings -- published July 29 in the journal Nature Microbiology -- provide clues as to why some viruses have greater "pandemic potential" than others and how researchers might go about identifying those that do before they become widespread.

For a virus to cause a pandemic it needs to be able to transmit between people, enter human cells, evade the body's defense systems, and cause disease. SARS-CoV-2, the virus that precipitated the COVID-19 pandemic, has been able to do all of this. But it's not yet clear why it is so efficient.

"We don't know what makes a virus have pandemic potential," said Mario Peña-Hernández, a Yale Ph.D. student in the labs of Akiko Iwasaki and Craig Wilen and lead author of the study. "These bat strains are 97% identical to SARS-CoV-2 genetically and we thought that, because they are the virus's closest known relatives, their phenotypic behavior -- or the way they infect and cause disease -- would be similar to SARS-CoV-2. But we found that wasn't true."

While the bat coronaviruses were able to efficiently enter some human cells and evade defense systems (often better than SARS-CoV-2 does), they did not transmit, or spread, well between hamsters and caused more mild disease in mice.

"The findings show us that we cannot tell from genomes alone what virus strains have the capacity to create a pandemic," said Peña-Hernández.

Other authors included Iwasaki, Sterling Professor of Immunobiology at Yale School of Medicine (YSM) and professor of epidemiology (microbial diseases) at Yale School of Public Health, and Wilen, an associate professor of laboratory medicine and of immunobiology at YSM.

For the study, the researchers used copies of the two bat coronaviruses and tested how well they were able to infect lab-cultured human respiratory tract cells and rodents. The work was done under the university's highest standard of biosafety. (Specifically, it was conducted under what is characterized as biosafety level 3+, requirements for which include restricted lab access, specialized personal protective equipment and respirators, and for experiments to be performed in biocontainment cabinets in a negative pressure facility).

The researchers found that while the two bat coronaviruses were effective at infecting cells isolated from the human bronchus -- the airway that connects the trachea to the lung -- they did not replicate well in cells from the nose.

"This is important to know, as most virus transmissions likely happen in the nose," said Iwasaki, a senior author of the study. "That these viruses don't replicate in the nose as well as SARS-CoV-2 could be an important indicator of why they failed to transmit in the animal models." The body has two types of immune protection: innate immunity -- a broad, general, first line of defense -- and adaptive immunity, which develops over time and can protect against more specific pathogens that individuals have already been exposed to. Innate immunity is particularly important against novel viruses to which people may have no adaptive immunity. In the study, the researchers found that the two bat coronaviruses were able to evade certain innate immunity molecules that fight infections.

"So the viruses can infect airway cells and dodge the body's defenses, yet they still failed to transmit between animals," said Wilen, a senior author of the study. "SARS-CoV-2 could evade innate immunity and transmit, so this suggested to us that these bat coronaviruses lack something that SARS-CoV-2 has."

One thing missing from these viruses is a molecular bit known as a "furin cleavage site." In SARS-CoV-2 and some other viruses, the spike protein of the virus can be cut by an enzyme called furin in order for the virus to efficiently enter human cells. Previous studies have found that mutated versions of SARS-CoV-2 lacking this site are less easily transmitted and cause less severe disease. In the new study, the researchers also found SARS-CoV-2 without this cleavage site didn't replicate as well in nasal cells, much like the two bat coronaviruses. In hamsters, viruses that lacked furin cleavage sites were quickly outcompeted by those that had them.

Whether a virus has this cleavage site could be one feature to look out for in the search to identify viral threats, said the researchers. However, it is likely that other viral features from this family of viruses also confer transmission or disease-causing potential. This, they said, highlights the importance of studying these viruses in the laboratory to identify these features. For example, how well a virus replicates in nasal cells could also serve as a proxy for assessing its transmission capacity.

Overall, the findings indicate that these two bat coronaviruses pose a more modest threat to humans, although it is possible that small genetic changes in these or similar viruses may evolve and significantly enhance pandemic risk. However, even in the event that the viruses did cross over to humans, the researchers found that adaptive immunity against SARS-CoV-2 was protective; blood sera samples taken from individuals who were vaccinated against or previously infected by SARS-CoV-2 neutralized the viruses.

"But understanding whether viruses have the potential to transmit between humans is important," said Iwasaki, who is also a professor of dermatology at YSM, a professor of molecular, cellular, and developmental biology in Yale's Faculty of Arts and Sciences, and an investigator of the Howard Hughes Medical Institute.

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Virus that causes COVID-19 is widespread in wildlife, scientists find

SARS-CoV-2, the virus responsible for COVID-19, is widespread among wildlife species, according to Virginia Tech research published Monday (July 29, 2024) in Nature Communications. The virus was detected in six common backyard species, and antibodies indicating prior exposure to the virus were found in five species, with rates of exposure ranging from 40 to 60 percent depending on the species.

Genetic tracking in wild animals confirmed both the presence of SARS-CoV-2 and the existence of unique viral mutations with lineages closely matching variants circulating in humans at the time, further supporting human-to-animal transmission, the study found.

The highest exposure to SARS CoV-2 was found in animals near hiking trails and high-traffic public areas, suggesting the virus passed from humans to wildlife, according to scientists at the Fralin Biomedical Research Institute at VTC, the Department of Biological Sciences in Virginia Tech's College of Science, and the Fralin Life Sciences Institute.

The findings highlight the identification of novel mutations in SARS-CoV-2 in wildlife and the need for broad surveillance, researchers say. These mutations could be more harmful and transmissible, creating challenges for vaccine development.

The scientists stressed, however, that they found no evidence of the virus being transmitted from animals to humans, and people should not fear typical interactions with wildlife.

Investigators tested animals from 23 common Virginia species for both active infections and antibodies indicating previous infections. They found signs of the virus in deer mice, Virginia opossums, raccoons, groundhogs, Eastern cottontail rabbits, and Eastern red bats. The virus isolated from one opossum showed viral mutations that were previously unreported and can potentially impact how the virus affects humans and their immune response.

"The virus can jump from humans to wildlife when we are in contact with them, like a hitchhiker switching rides to a new, more suitable host," said Carla Finkielstein, professor of biological sciences at the Fralin Biomedical Research Institute at VTC and one of the paper's corresponding authors. "The goal of the virus is to spread in order to survive. The virus aims to infect more humans, but vaccinations protect many humans. So, the virus turns to animals, adapting and mutating to thrive in the new hosts."

SARS CoV-2 infections were previously identified in wildlife, primarily in white-tailed deer and feral mink. The Virginia Tech study significantly expands the number of species examined and the understanding of virus transmission to and among wildlife. The data suggests exposure to the virus has been widespread in wildlife and that areas with high human activity may serve as points of contact for cross-species transmission.

"This study was really motivated by seeing a large, important gap in our knowledge about SARS-CoV-2 transmission in a broader wildlife community," said Joseph Hoyt, assistant professor of Biological Sciences in Virginia Tech's College of Science and corresponding author on the paper. "A lot of studies to date have focused on white-tailed deer, while what is happening in much of our common backyard wildlife remains unknown."

The research team collected 798 nasal and oral swabs across in Virginia from animals either live-trapped in the field and released, or being treated by wildlife rehabilitation centers. The team also obtained 126 blood samples from six species. The locations were chosen to compare the presence of the virus in animals in sites with varying levels of human activity, from urban areas to remote wilderness.

The study also identified two mice at the same site on the same day with the exact same variant, indicating they either both got it from the same human, or one infected the other.

Researchers are not certain about the means of transmission from humans to animals. One possibility is wastewater, but the Virginia Tech scientists believe trash receptacles and discarded food are more likely sources.

"I think the big take home message is the virus is pretty ubiquitous," said Amanda Goldberg, a former postdoctoral associate in Hoyt's lab, who is the study's first author. "We found positives in a large suite of common backyard animals."

While this study focused on the state of Virginia, many of the species that tested positive are common wildlife found throughout North America. It is likely they are being exposed in other areas as well, and surveillance across a broader region is urgently needed, Hoyt said.

"The virus is indifferent to whether its host walks on two legs or four. Its primary objective is survival. Mutations that do not confer a survival or replication advantage to the virus will not persist and will eventually disappear," said Finkielstein, who is also director of the Virginia Tech Molecular Diagnostics Lab. The Roanoke lab was established in April 2020 to expand COVID-19 testing.

"We understood the critical importance of sequencing the genome of the virus infecting those species," Finkielstein said. "It was a monumental task that could only be accomplished by a talented group of molecular biologists, bioinformaticians, and modelers in a state-of-the-art facility. I am proud of my team and my collaborators, their professionalism, and everything they contributed to ensure our success."

Surveillance for these mutations should continue and not be dismissed, the scientists said. More research is needed about how the virus is transmitted from humans to wildlife, how it might spread within a species, and perhaps from one species to another.

"This study highlights the potentially large host range SARS-CoV-2 can have in nature and really how widespread it might be," Hoyt said. "There is a lot of work to be done to understand which species of wildlife, if any, will be important in the long-term maintenance of SARS-CoV-2 in humans."

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How evolution tamed a deadly virus and why we should still worry

The story of the rise and fall of western equine encephalitis as a lethal disease offers essential lessons about how a pathogen can gain or lose its ability to jump from animals to humans.

That story is captured in newly published research from Harvard Medical School that identifies the mechanisms the western equine encephalitis virus used to infect humans and matches changes in that ability over time to a decline in illness and deaths caused by the pathogen.

The study results, published July 24 in Nature, offer important lessons for public health experts looking to prepare for future outbreaks, the researchers said.

The work took many unexpected turns, the researchers said. The findings challenge some of the basic assumptions that scientists have relied on in their attempts to understand how viruses interact with human cells and what causes outbreaks to ebb and flow, such as the notion that any given virus targets one host receptor to gain entry and infect cells.

"This was a real scientific detective story," said study senior author Jonathan Abraham, associate professor of microbiology in the Blavatnik Institute at Harvard Medical School. "The virus kept surprising us and taught us some important lessons about how to study viruses."

The researchers identified the specific proteins expressed on host cells that different strains of the virus have used to infect a variety of animals, including horses, humans, and birds over the last century. Their findings tied differences in the virus's ability to sicken humans and horses to changes in the viral genome that left the virus unable to target proteins found in humans and horses, while leaving intact the virus's ability to infect birds and reptiles that serve as reservoirs for the virus.

The surprising diversity and variability in the virus's ability to infect host cells highlights the importance of studying viruses broadly across time, space, and host species to track potential outbreaks and monitor for emerging and re-emerging viruses.

A virus changes

The protagonist in the story is the western equine encephalitis virus (WEEV), a member of a viral family known as alphaviruses.

One key to understanding how a virus interacts with a host is identifying the precise path it takes to enter cells and cause infection.

WEEV and others in the alphavirus family typically attach a spike protein to a compatible protein -- the receptor -- on the surface of a host cell. Once attached to the host receptor, the virus enters the cell. Once inside the cell, the virus hijacks the cells' armamentarium to enable its own replication, spread, and survival.

The researchers made harmless replicas of various viral strains collected from different times and places and tested their ability to infect host cells in lab dishes. They also tested some of the strains in mice.

Several deadly strains of WEEV are known to cause severe brain inflammation in both horses and humans. Some years, thousands of horses were killed and hundreds of humans were sickened. Case fatality rates for people were as high as 15 percent in North America in the early and middle decades of the 20th century.

Abraham's group found that some of these early strains could stick their spike proteins to several different types of receptors to enter animal cells. That was an unexpected finding because the prevailing dogma in virology thus far has been that viruses typically attack by targeting only one type of host cell receptor.

The team observed that the strains circulating during the years of frequent outbreaks could use multiple receptors that are expressed on brain cells of humans and horses, including proteins known as PCDH10 and VLDLR.

Although the virus still circulates between birds, mosquitoes, and other animals, the most recent outbreak in the United States in humans was in 1987, according to the Centers for Disease Control and Prevention. Since then, there have been only five cases identified in the United States.

By contrast, when the researchers tested more recently isolated strains recovered from mosquitos in California in 2005, they found that the viral spike protein failed to recognize the human receptors, but could still interact with similar proteins found in birds.

Based on these findings, the researchers hypothesize that the virus had evolved, perhaps because horses can be vaccinated and are no longer prevalent enough in the agriculture or transportation industries to serve as effective amplifiers for the virus. Alternatively, the researchers note, the virus may have evolved through simple antigenic drifting, a process by which random mutations cause a series of small changes to a viral genome that, over time, may end up changing the way a virus interacts with its host. Whatever the reason, the researchers said, subtle shifts in the shape of the viral spike proteins changed the cellular receptors with which the virus could connect.

This change in targetable host receptors is likely the central reason why the virus "submerged" as a human pathogen in North America, the research team said. This newly gleaned appreciation of the dynamic complexity of viral receptors is an essential tool for understanding how this virus or others like it might one day re-emerge, the scientists said.

"We need to understand what happens to viruses when they submerge, to better prepare for when they re-emerge," said first author Wanyu Li, a Harvard Kenneth C. Griffin Graduate School of Arts and Sciences doctoral student in the virology program in the Harvard Division of Medical Sciences at HMS.

For example, knowing whether dangerous versions of the pathogen persist in isolated populations of insects, or if the virus has gained the ability to infect other animals, could provide important early warning signs for potential resurgences of illnesses that are thought to have disappeared.

A virus's complex behavior

Through their experiments, the researchers discovered that certain old WEEV strains behaved differently than expected.

The team used eastern equine encephalitis virus -- a deadlier cousin of WEEV -- as a control in some experiments. In one test, the team found that an old strain of WEEV could use the same receptor as the eastern virus, which is something that newer WEEV strains could not do. They also found different strains of WEEV that used different receptors. Some strains could stick to avian versions of the receptor protein but not those expressed in human or equine cells.

The findings serve as an important reminder that viruses are part of a dynamic system and that the viruses themselves are dynamic, with subtle but significant differences across time and geography -- a notion that was powerfully underscored by the rapidly shapeshifting SARS-CoV-2 virus that fueled the COVID-19 pandemic, the researchers said.

"It was a wake-up call," Abraham said. "It's telling us that we can't just study one strain of a virus and assume we know the whole story. Viruses seem simple, but they're quite complex, and they're constantly changing."

Applying lessons to pandemic preparedness

In standard virology, researchers often only check a limited number of viral strains. These new findings show that that's not enough to truly understand the virus.

"There's so much more biology to be learned by exploring the diversity of these complex systems," Abraham said. He also noted that it's necessary to explore as much of that viral diversity as possible in order to prepare for possible outbreaks.

Many viruses circulate in insects and animals that live around us, Abraham said. Some, like the tick-borne infection Powassan, which is endemic in New England, occasionally flare up to cause deadly or debilitating disease.

There could be many reasons for the flare-ups, Abraham said. Are there different strains of Powassan that carry different levels of risk? Is it an environmental change or an evolutionary shift in the pathogen itself that causes new outbreaks? Looking at all these aspects and the breadth of viral diversity will help researchers predict and protect against outbreaks.

In another twist, as Abraham and his team conducted their experiments, a new outbreak of WEEV occurred in South America, which had also seen steep declines in the disease in recent years. The viral populations in South and North America appear to be genetically distinct, and the South American strain of the virus doesn't remain viable long enough for migrating birds to transfer it from one continent to the other regularly. Still, Abraham noted, the new outbreak in South America emphasizes the importance of vigilance and of improving scientific understanding of these volatile, shapeshifting viruses.

"WEEV's return caught everyone by surprise," Li said. "Now with its cellular host receptors known, we have the tools to understand the molecular aspects of WEEV's re-emergence."

Abraham and collaborators are now investigating the strains associated with recent outbreak in South America.

"One small shift in the viral genome, in the intensity of a rainy season that allows mosquitos to proliferate, or in the place humans live or work, could trigger an outbreak," Abraham said. "The more we know, the better we'll be able to protect ourselves."

Read more at Science Daily

Study shows promise for a universal influenza vaccine

New research led by Oregon Health & Science University reveals a promising approach to developing a universal influenza vaccine -- a so-called "one and done" vaccine that confers lifetime immunity against an evolving virus.

The study, published today in the journal Nature Communications, tested an OHSU-developed vaccine platform against the virus considered most likely to trigger the next pandemic.

Researchers reported the vaccine generated a robust immune response in nonhuman primates that were exposed to the avian H5N1 influenza virus. But the vaccine wasn't based on the contemporary H5N1 virus; instead, the primates were inoculated against the influenza virus of 1918 that killed millions of people worldwide.

"It's exciting because in most cases, this kind of basic science research advances the science very gradually; in 20 years, it might become something," said senior author Jonah Sacha, Ph.D., professor and chief of the Division of Pathobiology at OHSU's Oregon National Primate Research Center. "This could actually become a vaccine in five years or less."

Researchers reported that six of 11 nonhuman primates inoculated against the virus that circulated a century ago -- the 1918 flu -- survived exposure to one of the deadliest viruses in the world today, H5N1. In contrast, a control group of six unvaccinated primates exposed to the H5N1 virus succumbed to the disease.

Sacha said he believes the platform "absolutely" could be useful against other mutating viruses, including SARS-CoV-2.

"It's a very viable approach," he said. "For viruses of pandemic potential, it's critical to have something like this. We set out to test influenza, but we don't know what's going to come next."

A senior co-author from the University of Pittsburgh concurred.

"Should a deadly virus such as H5N1 infect a human and ignite a pandemic, we need to quickly validate and deploy a new vaccine," said co-corresponding author Douglas Reed, Ph.D., associate professor of immunology at the University of Pittsburgh Center for Vaccine Research.

Finding a stationary target

This approach harnesses a vaccine platform previously developed by scientists at OHSU to fight HIV and tuberculosis, and in fact is already being used in a clinical trial against HIV.

The method involves inserting small pieces of target pathogens into the common herpes virus cytomegalovirus, or CMV, which infects most people in their lifetimes and typically produces mild or no symptoms. The virus acts as a vector specifically designed to induce an immune response from the body's own T cells.

This approach differs from common vaccines -- including the existing flu vaccines -- which are designed to induce an antibody response that targets the most recent evolution of the virus, distinguished by the arrangement of proteins covering the exterior surface.

"The problem with influenza is that it's not just one virus," Sacha said. "Like the SARS-CoV-2 virus, it's always evolving the next variant and we're always left to chase where the virus was, not where it's going to be."

The spike proteins on the virus exterior surface evolve to elude antibodies. In the case of flu, vaccines are updated regularly using a best estimate of the next evolution of the virus. Sometimes it's accurate, sometimes less so.

In contrast, a specific type of T cell in the lungs, known as effector memory T cell, targets the internal structural proteins of the virus, rather than its continually mutating outer envelope. This internal structure doesn't change much over time -- presenting a stationary target for T cells to search out and destroy any cells infected by an old or newly evolved influenza virus.

Success with a century-old template

To test their T cell theory, researchers designed a CMV-based vaccine using the 1918 influenza virus as a template. Working within a highly secure biosafety level 3 laboratory at the University of Pittsburgh, they exposed the vaccinated nonhuman primates to small particle aerosols containing the avian H5N1 influenza virus -- an especially severe virus that is currently circulating among dairy cows in the United States.

Remarkably, six of the 11 vaccinated primates survived the exposure, despite the century-long period of virus evolution.

"It worked because the interior protein of the virus was so well preserved," Sacha said. "So much so, that even after almost 100 years of evolution, the virus can't change those critically important parts of itself."

The study raises the potential for developing a protective vaccine against H5N1 in people.

"Inhalation of aerosolized H5N1 influenza virus causes a cascade of events that can trigger respiratory failure," said co-senior author Simon Barratt-Boyes, Ph.D., professor of infectious diseases, microbiology and immunology at Pitt. "The immunity induced by the vaccine was sufficient to limit virus infection and lung damage, protecting the monkeys from this very serious infection."

By synthesizing more up-to-date virus templates, the new study suggests CMV vaccines may be able to generate an effective, long-lasting immune response against a wide suite of new variants.

"I think it means within five to 10 years, a one-and-done shot for influenza is realistic," Sacha said.

The same CMV platform developed by OHSU researchers has advanced to a clinical trial to protect against HIV, and a recent publication by those scientists suggests it may even be useful targeting specific cancer cells. The HIV clinical trial is being led by Vir Biotechnology, which licensed the vaccine platform from OHSU.

Sacha sees the development as the latest in the rapid advance of medical research to treat or prevent disease.

"It's a massive sea change within our lifetimes," Sacha said. "There is no question we are on the cusp of the next generation of how we address infectious disease."

Read more at Science Daily

A virus could help save billions of gallons of wastewater produced by fracking

An estimated 168 billion gallons of wastewater -- or produced water -- is generated annually by the Permian Basin fracking industry, according to a 2022 report by the Texas Produced Water Consortium. The major waste stream has proved both difficult and costly to treat because of the chemical complexity of the water.

In a new study published in the journal Water, researchers at The University of Texas at El Paso have identified a novel means of treating the wastewater generated by oil and gas production: bacteriophages.

Ramón Antonio Sánchez, a doctoral candidate within UTEP's chemistry program, is the first author on the publication, detailing how bacteriophages, viruses that are often highly specific and lethal to a single species of bacteria, can be used as a rapid and cost-effective method to treat produced water on an industrial scale.

Sánchez said if the work is successful, it would give the oil and gas industry a means of treating, reusing and recycling produced water, rather than the current industry practice of disposing the majority of produced water by injecting it into the ground post oil exploration.

The research focuses on two of the most prominent bacteria found within produced water across the oil and gas industry -- Pseudomonas aeruginosa and Bacillus megaterium. P. aeruginosa has the ability to corrode stainless steel and presents a challenge for the longevity of pipelines and other metal-based infrastructure, while B. megaterium, can decompose hydrocarbons -- the basis for oil.

Sánchez, along with one of his collaborators, Zacariah Hildenbrand, Ph.D., a UTEP alum, were inspired to use bacteriophages based on their applications in the medical industry, where they are used to combat infections caused by multi-drug resistant bacteria.

"Since the bacteria are living organisms, over time they developed a resistance, in the form of a less penetrable membrane, to traditional disinfectants," Sánchez explained. "But the bacteriophages, which are viruses themselves, attach to specific receptors on the surface of the host cell and evolve alongside the bacteria they are trying to infect, meaning that any resistance acquired by the bacteria triggers the modification of bacteriophages to keep the infection going."

The team's experiments with bacteriophages have been effective, achieving the inactivation of both P. aeruginosa and B. megaterium in laboratory settings. For Sánchez, who graduates this spring with his Ph.D., the work will continue in the industry where his focus will be on replicating his laboratory results out in the field. He will also try to expand the number of microorganisms that can be treated in produced water by securing a larger catalog of bacteriophages.

Read more at Science Daily

Honey bees experience multiple health stressors out-in-the-field

It's not a single pesticide or virus stressing honey bees, and affecting their health, but exposure to a complex web of multiple interacting stressors encountered while at work pollinating crops, found new research out of York University.

Scientists have been unable to explain increasing colony mortality, even after decades of research examining the role of specific pesticides, parasitic mites, viruses or genetics. This led the research team to wonder if previous studies were missing something by focussing on one stressor at a time.

"Our study is the first to apply systems level or network analyses to honey bee stressors at a massive scale. I think this represents a paradigm shift in the field because we have been so focussed on finding the one big thing, the smoking gun," says corresponding author of the new paper York Faculty of Science Professor Amro Zayed, York Research Chair in Genomics. "But we are finding that bees are exposed to a very complicated network of stressors that change quickly over time and space. It's a level of complexity that we haven't thought about before. To me, that's the big surprise of this study."

The paper, Honey bee stressor networks are complex and dependent on crop and region, published today in Current Biology, takes a much broader look at the interplay of stressors and their effects. The study team also included researchers from the University of British Columbia, Agriculture and Agri-Food Canada, the University of Victoria, the University of Lethbridge, the University of Manitoba, l'Université Laval, the University of Guelph, and the Ontario Beekeepers' Association.

Not all stressors are the same, however. Some stressors are more influential than others -- what researchers call the social media influencers of the bee world -- having an outsized impact on the architecture of a highly complex network and their co-stressors. They also found that most of these influencer stressors are viruses and pesticides that regularly show up in combination with specific other stressors, compounding the negative effects through their interactions.

"Understanding which stressors co-occur and are likely to interact is profoundly important to unravelling how they are impacting the health and mortality of honey bee colonies," says lead author, York Postdoctoral Fellow Sarah French of the Faculty of Science.

"There have been a lot of studies about major pesticides, but in this research, we also saw a lot of minor pesticides that we don't usually think about or study. We also found a lot of viruses that beekeepers don't typically test for or manage. Seeing the influencer stressors interact with all these other stressors, whether it be mites, other pesticides or viruses, was not only interesting, but surprising."

French says the way influencer stressors co-occur with other stressors is similar to the way humans experience co-morbidities, such as when someone is diagnosed with heart disease. They are more likely to also have diabetes or high blood pressure or both, and each one impacts the other. "That's similar to the way we examine bee colonies. We look at everything that's going on in the colony and then compare or amalgamate all the colonies together to look at the broader patterns of what is happening and how everything is related. Two or multiple stressors can really synergize off each other leading to a much greater effect on bee health."

From Québec to British Columbia, honey bee colonies were given the job of pollinating some of Canada's most valuable crops -- apples, canola oil and seed, highbush and lowbush blueberry, soybean, cranberry and corn. The study covered multiple time scales, providing numerous snapshots, rather than the usual single snapshot in time. The research team found that honey bees were exposed to an average of 23 stressors at once that combined to create 307 interactions.

Honey bees are a billion dollar industry. In 2021, honey bees contributed some $7 billion in economic value by pollinating orchards, vegetables, berries and oil seeds like canola, and produced 75 to 90 million pounds of honey. Figuring which stressors would provide the most benefit if managed would go a long way toward developing the right tools to tackle them, something beekeepers are often lacking.

The research is part of the BEECSI: 'OMIC tools for assessing bee health project funded to the tune of $10 million by Genome Canada in 2018 to use genomic tools to develop a new health assessment and diagnosis platform powered by stressor-specific markers.

More research is needed to unravel how the stressors are interacting and impacting honey bee mortality and colony health going forward, says French. "It's really teasing apart which of these compounds might have that relationship and how can we build off this to study those specific relationships."

It can't come soon enough, honey bees are currently facing poor health, colony loss, parasites, pathogens and heightened stressors worldwide. Some beekeepers in this country and the United States face a loss over winter of up to 60 per cent of their colonies.

Read more at Science Daily

Viruses that can help 'dial up' carbon capture in the sea

Armed with a catalog of hundreds of thousands of DNA and RNA virus species in the world's oceans, scientists are now zeroing in on the viruses most likely to combat climate change by helping trap carbon dioxide in seawater or, using similar techniques, different viruses that may prevent methane's escape from thawing Arctic soil.

By combining genomic sequencing data with artificial intelligence analysis, researchers have identified ocean-based viruses and assessed their genomes to find that they "steal" genes from other microbes or cells that process carbon in the sea. Mapping microbial metabolism genes, including those for underwater carbon metabolism, revealed 340 known metabolic pathways throughout the global oceans. Of these, 128 were also found in the genomes of ocean viruses.

"I was shocked that the number was that high," said Matthew Sullivan, professor of microbiology and director of the Center of Microbiome Science at The Ohio State University.

Having mined this massive trove of data via advances in computation, the team has now revealed which viruses have a role in carbon metabolism and are using this information in newly developed community metabolic models to help predict how using viruses to engineer the ocean microbiome toward better carbon capture would look.

"The modeling is about how viruses may dial up or dial down microbial activity in the system," Sullivan said. "Community metabolic modeling is telling me the dream data point: which viruses are targeting the most important metabolic pathways, and that matters because it means they're good levers to pull on."

Sullivan presented the research today (Feb. 17, 2024) at the annual meeting of the American Association for the Advancement of Science in Denver.

Sullivan was the virus coordinator for the Tara Oceans Consortium, a three-year global study of the impact of climate change on the world's oceans and the source of 35,000 water samples containing the microbial bounty. His lab focuses on phages, viruses that infect bacteria, and their potential to be scaled up in an engineering framework to manipulate marine microbes into converting carbon into the heaviest organic form that will sink to the ocean floor.

"Oceans soak up carbon, and that buffers us against climate change. CO2 is absorbed as a gas, and its conversion into organic carbon is dictated by microbes," Sullivan said. "What we're seeing now is that viruses target the most important reactions in these microbial community metabolisms. This means we can start investigating which viruses could be used to convert carbon toward the kind we want.

"In other words, can we strengthen this massive ocean buffer to be a carbon sink to buy time against climate change, as opposed to that carbon being released back into the atmosphere to accelerate it?"

In 2016, the Tara team determined that carbon sinking in the ocean was related to the presence of viruses. It is thought that viruses help sink carbon when virus-infected carbon-processing cells cluster into larger, sticky aggregates that drop to the ocean floor. The researchers developed AI-based analytics to identify from thousands of viruses which few are "VIP" viruses to culture in the lab and work with as model systems for ocean geoengineering.

This new community metabolic modeling, developed by collaborator Professor Damien Eveillard of the Tara Oceans Consortium, helps them understand what unintended consequences might be of such an approach. Sullivan's lab is taking these oceanic lessons learned and applying them to using viruses to engineer microbiomes in human settings to aid recovery from spinal cord injury, improve outcomes for infants born to mothers with HIV, combat infection in burn wounds, and more.

"The conversation we're having is, 'How much of this is transferable?'" said Sullivan, also a professor of civil, environmental and geodetic engineering. "The overall goal is engineering microbiomes toward what we think is something useful."

He also reported on early efforts to use phages as geoengineering tools in an entirely different ecosystem: the permafrost in northern Sweden, where microbes both change the climate and respond to climate change as the frozen soil thaws. Virginia Rich, associate professor of microbiology at Ohio State, is co-director of the National Science Foundation-funded EMERGE Biology Integration Institute based at Ohio State that organizes the microbiome science at the Sweden field site. Rich also co-led previous research that identified a lineage of single-cell organisms in the thawing permafrost soil as a significant producer of methane, a potent greenhouse gas.

Rich co-organized the AAAS session with Ruth Varner of the University of New Hampshire, who co-directs the EMERGE Institute, which is focusing on better understanding how microbiomes respond to permafrost thaw and the resulting climate interactions.

Sullivan's talk was titled "From ecosystems biology to managing microbiomes with viruses," and was presented at the session titled "Microbiome-Targeted Ecosystem Management: Small Players, Big Roles."

Read more at Science Daily

'Long flu' has emerged as a consequence similar to long COVID

Since the COVID-19 pandemic began, extensive research has emerged detailing the virus's ability to attack multiple organ systems, potentially resulting in a set of enduring and often disabling health problems known as long COVID. Now, new research from Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care System indicates that people hospitalized with seasonal influenza also can suffer long-term, negative health effects, especially involving their lungs and airways.

The new study comparing the viruses that cause COVID-19 and the flu also revealed that in the 18 months after infection, patients hospitalized for either COVID-19 or seasonal influenza faced an increased risk of death, hospital readmission, and health problems in many organ systems. Further, the time of highest risk was 30 days or later after initial infection.

"The study illustrates the high toll of death and loss of health following hospitalization with either COVID-19 or seasonal influenza," said senior author Ziyad Al-Aly, MD, a clinical epidemiologist at Washington University. "It's critical to note that the health risks were higher after the first 30 days of infection. Many people think they're over COVID-19 or the flu after being discharged from the hospital. That may be true for some people. But our research shows that both viruses can cause long-haul illness."

The findings are published Dec. 14 in The Lancet Infectious Diseases.

The statistical analysis spanned up to 18 months post-infection and included a comparative evaluation of risks of death, hospital admissions and 94 adverse health outcomes involving the body's major organ systems.

"A review of past studies on COVID-19 versus the flu focused on a short-term and narrow set of health outcomes," said Al-Aly, who treats patients within the VA St. Louis Health Care System and is an assistant professor of medicine at Washington University. "Our novel approach compared the long-term health effects of a vast array of conditions. Five years ago, it wouldn't have occurred to me to examine the possibility of a 'long flu.' A major lesson we learned from SARS-CoV-2 is that an infection that initially was thought to only cause brief illness also can lead to chronic disease. This revelation motivated us to look at long-term outcomes of COVID-19 versus flu.

"We wanted to know whether and to what degree people with flu also experience long-term health effects," Al-Aly said. "The big answer is that both COVID-19 and the flu led to long-term health problems, and the big aha moment was the realization that the magnitude of long-term health loss eclipsed the problems that these patients endured in the early phase of the infection. Long COVID is much more of a health problem than COVID, and long flu is much more of a health problem than the flu."

However, the overall risk and occurrence of death, hospital admissions, and loss of health in many organ systems are substantially higher among COVID-19 patients than among those who have had seasonal influenza, Al-Aly said. "The one notable exception is that the flu poses higher risks to the pulmonary system than COVID-19," he said. "This tells us the flu is truly more of a respiratory virus, like we've all thought for the past 100 years. By comparison, COVID-19 is more aggressive and indiscriminate in that it can attack the pulmonary system, but it can also strike any organ system and is more likely to cause fatal or severe conditions involving the heart, brain, kidneys and other organs."

The researchers analyzed de-identified medical records in a database maintained by the U.S. Department of Veterans Affairs, the nation's largest integrated health-care delivery system. They evaluated information involving 81,280 patients hospitalized for COVID-19 at some point from March 1, 2020, through June 30, 2022, as well as 10,985 patients hospitalized for seasonal influenza at some point from Oct. 1, 2015, through Feb. 28, 2019.

Patients represented multiple ages, races and sexes.

Regarding both viruses, patient vaccination status did not affect results. Those in the COVID-19 cohort were hospitalized during the pre-delta, delta and omicron eras.

During the overall 18-month study period, patients who had COVID-19 faced a 50% higher risk of death than those with seasonal influenza. This corresponded to about eight more deaths per 100 persons in the COVID-19 group than among those with the flu.

Although COVID-19 showed a greater risk of health loss than seasonal influenza, infection with either virus carried significant risk of disability and disease. The researchers found COVID-19 exhibited increased risk of 68% of health conditions examined across all organ systems (64 of the 94 adverse health outcomes studied), while the flu was associated with elevated risk of 6% of health conditions (six of the 94) -- mostly in the respiratory system.

Also, over 18 months, COVID-19 patients experienced an increased risk of hospital readmission as well as admission to an intensive care unit (ICU). For every 100 persons in each group, there were 20 more hospital admissions and nine more ICU admissions in COVID-19 than flu.

"Our findings highlight the continued need to reduce the risk of hospitalization for these two viruses as a way to alleviate the overall burden of health loss in populations," Al-Aly said. "For both COVID-19 and seasonal influenza, vaccinations can help prevent severe disease and reduce the risk of hospitalizations and death. Optimizing vaccination uptake must remain a priority for governments and health systems everywhere. This is especially important for vulnerable populations such as the elderly and people who are immunocompromised."

In both COVID-19 and the flu, more than half of death and disability occurred in the months after infection as opposed to the first 30 days, the latter of which is known as the acute phase.

Read more at Science Daily

Movement sensors can detect disease in wild boar

Behavioral sensors attached to wild boars have been used to detect when animals are sick with African Swine Fever, a fatal viral disease that affects both boar and domestic pigs. Accelerometer sensors, which measure tiny changes in movement, showed that wild boars reduced their daily activity by up to 20 percent when infected with the virus. The findings, published by scientists from the Max Planck Institute of Animal Behavior, show that lightweight sensors can detect sickness behavior in wild boar -- raising the possibility of a minimally invasive tool to assist in the control and prevention of African Swine Fever.

Although the virus cannot be transmitted to humans, African Swine Fever is a major threat to the global pig industry and has significant economic and social impact. The highly contagious virus spreads easily between wild boar and domestic pigs, and so knowing when a disease outbreak occurs in the wild and on farms is important for curbing the spread of African Swine Fever. But detecting disease in wild animals is not straight forward. Currently, testing for African Swine Fever in wild boar is done by sampling animals that are either hunted or found dead, which creates a long lag between when the disease emerges in a population to when it is actually detected.

Seeking to reduce this lag, scientists from Germany, Spain and Austria teamed up to investigate if technology that 'reads' an animal's behavior could be harnessed for early detection of disease in wild boar. Their findings point to the potential of accelerometer sensors as an accessible tool that can support the existing disease management approaches for African Swine Fever surveillance and control. "This is a game-changer for wildlife disease monitoring," says Kevin Morelle, first author of the study and a scientist with the Max Planck Institute of Animal Behavior. "We show that a lightweight behavioral sensor deployed on a wild animal can be a sentinel for potential health threats."

Accelometers measure animals' movements

The scientists attached accelerometer tags, weighting 30 grams, on twelve wild boars that were studied in controlled conditions. The boars were infected with African Swine Fever as part of a separate study aimed at developing a vaccine against the disease. The accelerometers, which are the equivalent of 'Fitbits' or pedometers, took ultra-high resolution measurements of the animals' movements. The measurements, called 'Overall Dynamic Body Acceleration', showed how much the boars were active. The scientists found that when boars became sick with African Swine Fever, they were ten to twenty percent less active daily than when they were healthy. To validate the findings, the study authors attached accelerometers to a group of healthy boars living in natural conditions. They then compared the activity patterns of infected and healthy wild boar.

Read more at Science Daily

Engineers design more powerful RNA vaccines

RNA vaccines against Covid-19 have proven effective at reducing the severity of disease. However, a team of researchers at MIT is working on making them even better. By tweaking the design of the vaccines, the researchers showed that they could generate Covid-19 RNA vaccines that produce a stronger immune response, at a lower dose, in mice.

Adjuvants are molecules commonly used to increase the immune response to vaccines, but they haven't yet been used in RNA vaccines. In this study, the MIT researchers engineered both the nanoparticles used to deliver the Covid-19 antigen, and the antigen itself, to boost the immune response, without the need for a separate adjuvant.

If further developed for use in humans, this type of RNA vaccine could help to reduce costs, reduce the dosage needed, and potentially lead to longer-lasting immunity. The researchers' tests also showed that when delivered intranasally, the vaccine induced a strong immune response when compared to the response elicited by traditional, intramuscular vaccination.

"With intranasal vaccination, you might be able to kill Covid at the mucus membrane, before it gets into your body," says Daniel Anderson, a professor in MIT's Department of Chemical Engineering, a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study. "Intranasal vaccines may also be easier to administer to many people, since they don't require an injection."

The researchers believe that the effectiveness of other types of RNA vaccines that are now in development, including vaccines for cancer, could be improved by incorporating similar immune-stimulating properties.

Former MIT postdoc Bowen Li, who is now an assistant professor at the University of Toronto; graduate student Allen Jiang; and former MIT postdoc Idris Raji, who was a research fellow at Boston Children's Hospital, are the lead authors of the new study, which appears today in Nature Biomedical Engineering. The research team also includes Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, and several other MIT researchers.

Boosting immunity

RNA vaccines consist of a strand of RNA that encodes a viral or bacterial protein, also called an antigen. In the case of Covid-19 vaccines, this RNA codes for a segment of the virus's spike protein. That RNA strand is packaged in a lipid nanoparticle carrier, which protects the RNA from being broken down in the body and helps it get into cells.

Once delivered into cells, the RNA is translated into proteins that the immune system can detect, generating antibodies and T cells that will recognize the protein if the person later becomes infected with the SARS-CoV-2 virus.

The original Covid-19 RNA vaccines developed by Moderna and Pfizer/BioNTech provoked strong immune responses, but the MIT team wanted to see if they could make them more effective by engineering them to have immune stimulatory properties.

In this study, the researchers employed two different strategies to boost the immune response. For the first, they focused on a protein called C3d, which is part of an arm of the immune response known as the complement system. This set of proteins helps the body fight off infection, and C3d's role is to bind to antigens and amplify the antibody response to those antigens. For many years, scientists have been evaluating the use of C3d as a molecular adjuvant for vaccines made from proteins, such as the DPT vaccine.

"With the promise of mRNA technologies being realized with the Covid vaccines, we thought that this would be a fantastic opportunity to see if C3d might also be able to play a role as an adjuvant in mRNA vaccine systems," Jiang says.

To that end, the researchers engineered the mRNA to encode the C3d protein fused to the antigen, so that both components are produced as one protein by cells that receive the vaccine.

In the second phase of their strategy, the researchers modified the lipid nanoparticles used to deliver the RNA vaccine, so that in addition to helping with RNA delivery, the lipids also intrinsically stimulate a stronger immune response.

To identify lipids that would work best, the researchers created a library of 480 lipid nanoparticles with different types of chemistries. All of these are "ionizable" lipids, which become positively charged when they enter acidic environments. The original Covid RNA vaccines also included some ionizable lipids because they help the nanoparticles to self-assemble with RNA and they help target cells to take up the vaccine.

"We understood that nanoparticles themselves could be immunostimulatory, but we weren't quite sure what the chemistry was that was needed to optimize that response. So instead of trying to make the perfect one, we made a library and evaluated them, and through that we identified some chemistries that seemed to improve their response," Anderson says.

Toward intranasal vaccines

The researchers tested their new vaccine, which included both RNA-encoded C3d and a top-performing ionizable lipid identified from their library screen, in mice. They found that mice injected with this vaccine produced 10 times more antibodies than mice given unadjuvanted Covid RNA vaccines. The new vaccine also provoked a stronger response among T cells, which play important roles in combating the SARS-CoV-2 virus.

"For the first time, we've demonstrated a synergistic boost in immune responses by engineering both the RNA and its delivery vehicles," Li says. "This prompted us to investigate the feasibility of administering this new RNA vaccine platform intranasally, considering the challenges presented by the mucociliary blanket barrier in the upper airways."

When the researchers delivered the vaccine intranasally, they observed a similarly strong immune response in the mice. If developed for use in people, an intranasal vaccine could potentially offer enhanced protection against infection because it would generate an immune response within the mucosal tissues that line the nasal passages and lungs.

Because self-adjuvanting vaccines elicit a stronger response at a lower dose, this approach could also help to reduce the cost of vaccine doses, which might allow them to reach more people, especially in developing nations, the researchers say.

Read more at Science Daily

Novel molecules fight viruses by bursting their bubble-like membranes

Antiviral therapies are notoriously difficult to develop, as viruses can quickly mutate to become resistant to drugs. But what if a new generation of antivirals ignores the fast-mutating proteins on the surface of viruses and instead disrupts their protective layers?

"We found an Achilles heel of many viruses: their bubble-like membranes. Exploiting this vulnerability and disrupting the membrane is a promising mechanism of action for developing new antivirals," said Kent Kirshenbaum, professor of chemistry at NYU and the study's senior author.

In a new study published Aug. 2 in the journal ACS Infectious Diseases, the researchers show how a group of novel molecules inspired by our own immune system inactivates several viruses, including Zika and chikungunya. Their approach may not only lead to drugs that can be used against many viruses, but could also help overcome antiviral resistance.

The urgent need for new antivirals

Viruses have different proteins on their surfaces that are often the targets of therapeutics like monoclonal antibodies and vaccines. But targeting these proteins has limitations, as viruses can quickly evolve, changing the properties of the proteins and making treatments less effective. These limitations were on display when new SARS-CoV-2 variants emerged that evaded both the drugs and the vaccines developed against the original virus.

"There is an urgent need for antiviral agents that act in new ways to inactivate viruses," said Kirshenbaum. "Ideally, new antivirals won't be specific to one virus or protein, so they will be ready to treat new viruses that emerge without delay and will be able to overcome the development of resistance."

"We need to develop this next generation of drugs now and have them on the shelves in order to be ready for the next pandemic threat -- and there will be another one, for sure," added Kirshenbaum.

Drawing inspiration from our immune systems

Our innate immune system combats pathogens by producing antimicrobial peptides, the body's first line of defense against bacteria, fungi, and viruses. Most viruses that cause disease are encapsulated in membranes made of lipids, and antimicrobial peptides work by disrupting or even bursting these membranes.

While antimicrobial peptides can be synthesized in the lab, they are rarely used to treat infectious diseases in humans because they break down easily and can be toxic to healthy cells. Instead, scientists have developed synthetic materials called peptoids, which have similar chemical backbones to peptides but are better able to break through virus membranes and are less likely to degrade.

"We began to think about how to mimic natural peptides and create molecules with many of the same structural and functional features as peptides, but are composed of something that our bodies won't be able to rapidly degrade," said Kirshenbaum.

The researchers investigated seven peptoids, many originally discovered in the lab of Annelise Barron at Stanford, a co-author of the study. The NYU team studied the antiviral effects of the peptoids against four viruses: three enveloped in membranes (Zika, Rift Valley fever, and chikungunya) and one without (coxsackievirus B3).

"We were particularly interested in studying these viruses as they have no available treatment options," said Patrick Tate, a chemistry PhD student at NYU and the study's first author.

How peptoids disrupt viral membranes and avoid other cells

The membranes surrounding viruses are made of different molecules than the virus itself, as lipids are acquired from the host to form membranes. One such lipid, phosphatidylserine, is present in the membrane on the outside of viruses, but is sequestered towards the interior of human cells under normal conditions.

"Because phosphatidylserine is found on the exterior of viruses, it can be a specific target for peptoids to recognize viruses, but not recognize -- and therefore spare -- our own cells," said Tate. "Moreover, because viruses acquire lipids from the host rather than encoding from their own genomes, they have better potential to avoid antiviral resistance."

The researchers tested seven peptoids against the four viruses. They found that the peptoids inactivated all three enveloped viruses -- Zika, Rift Valley fever, and chikungunya -- by disrupting the virus membrane, but did not disrupt coxsackievirus B3, the only virus without a membrane.

Moreover, chikungunya virus containing higher levels of phosphatidylserine in its membrane was more susceptible to the peptoids. In contrast, a membrane formed exclusively with a different lipid named phosphatidylcholine was not disrupted by the peptoids, suggesting that phosphatidylserine is crucial in order for peptoids to reduce viral activity.

"We're now starting to understand how peptoids actually exert their antiviral effect -- specifically, through the recognition of phosphatidylserine," said Tate.

The researchers are continuing pre-clinical studies to evaluate the potential of these molecules in fighting viruses and to understand if they can overcome the development of resistance. Their peptoid-focused approach may hold promise for treating a wide range of viruses with membranes that can be difficult to treat, including Ebola, SARS-CoV-2, and herpes.

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Research offers clues for potential widespread HIV cure in people

New research from Oregon Health & Science University is helping explain why at least five people have become HIV-free after receiving a stem cell transplant. The study's insights may bring scientists closer to developing what they hope will become a widespread cure for the virus that causes AIDS, which has infected about 38 million people worldwide.

Published today in the journal Immunity, the OHSU-led study describes how two nonhuman primates were cured of the monkey form of HIV after receiving a stem cell transplant. It also reveals that two circumstances must co-exist for a cure to occur and documents the order in which HIV is cleared from the body -- details that can inform efforts to make this cure applicable to more people.

"Five patients have already demonstrated that HIV can be cured," said the study's lead researcher, Jonah Sacha, Ph.D., a professor at OHSU's Oregon National Primate Research Center and Vaccine and Gene Therapy Institute.

"This study is helping us home in on the mechanisms involved in making that cure happen," Sacha continued. "We hope our discoveries will help to make this cure work for anyone, and ideally through a single injection instead of a stem cell transplant."

The first known case of HIV being cured through a stem cell transplant was reported in 2009. A man who was living with HIV was also diagnosed with acute myeloid leukemia, a type of cancer, and underwent a stem cell transplant in Berlin, Germany. Stem cell transplants, which are also called bone marrow transplants, are used to treat some forms of cancer. Known as the Berlin patient, he received donated stem cells from someone with a mutated CCR5 gene, which normally codes for a receptor on the surface of white blood cells that HIV uses to infect new cells. A CCR5 mutation makes it difficult for the virus to infect cells, and can make people resistant to HIV. Since the Berlin patient, four more people have been similarly cured.

This study was conducted with a species of nonhuman primate known as Mauritian cynomolgus macaques, which the research team previously demonstrated can successfully receive stem cell transplants. While all of the study's eight subjects had HIV, four of them underwent a transplant with stem cells from HIV-negative donors, and the other half served as the study's controls and went without transplants.

Of the four that received transplants, two were cured of HIV after successfully being treated for graft-versus-host disease, which is commonly associated with stem cell transplants.

Other researchers have tried to cure nonhuman primates of HIV using similar methods, but this study marks the first time that HIV-cured research animals have survived long term. Both remain alive and HIV-free today, about four years after transplantation. Sacha attributes their survival to exceptional care from Oregon National Primate Research Center veterinarians and the support of two study coauthors, OHSU clinicians who care for people who undergo stem cell transplants: Richard T. Maziarz, M.D., and Gabrielle Meyers, M.D.

"These results highlight the power of linking human clinical studies with pre-clinical macaque experiments to answer questions that would be almost impossible to do otherwise, as well as demonstrate a path forward to curing human disease," said Maziarz, a professor of medicine in the OHSU School of Medicine and medical director of the adult blood and marrow stem cell transplant and cellular therapy programs in the OHSU Knight Cancer Institute.

The how behind the cure

Although Sacha said it was gratifying to confirm stem cell transplantation cured the nonhuman primates, he and his fellow scientists also wanted to understand how it worked. While evaluating samples from the subjects, the scientists determined there were two different, but equally important, ways they beat HIV.

First, the transplanted donor stem cells helped kill the recipients' HIV-infected cells by recognizing them as foreign invaders and attacking them, similar to the process of graft-versus-leukemia that can cure people of cancer.

Second, in the two subjects that were not cured, the virus managed to jump into the transplanted donor cells. A subsequent experiment verified that HIV was able to infect the donor cells while they were attacking HIV. This led the researchers to determine that stopping HIV from using the CCR5 receptor to infect donor cells is also needed for a cure to occur.

The researchers also discovered that HIV was cleared from the subjects' bodies in a series of steps. First, the scientists saw that HIV was no longer detectable in blood circulating in their arms and legs. Next, they couldn't find HIV in lymph nodes, or lumps of immune tissue that contain white blood cells and fight infection. Lymph nodes in the limbs were the first to be HIV-free, followed by lymph nodes in the abdomen.

The step-wise fashion by which the scientists observed HIV being cleared could help physicians as they evaluate the effectiveness of potential HIV cures. For example, clinicians could focus on analyzing blood collected from both peripheral veins and lymph nodes. This knowledge may also help explain why some patients who have received transplants initially have appeared to be cured, but HIV was later detected. Sacha hypothesizes that those patients may have had a small reservoir of HIV in their abdominal lymph nodes that enabled the virus to persist and spread again throughout the body.

Sacha and colleagues continue to study the two nonhuman primates cured of HIV. Next, they plan to dig deeper into their immune responses, including identifying all of the specific immune cells involved and which specific cells or molecules were targeted by the immune system.

This research is supported by the National Institutes of Health (grants AI112433, AI129703, P51 OD011092) and the Foundation for AIDS Research (grant 108832), and the Foundation for AIDS Immune Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

In our interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regard to this research, Dr. Sacha has a significant financial interest in CytoDyn, a company that may have a commercial interest in the results of this research and technology. Review?details of OHSU's conflict of interest program?to find out more about how we manage these business relationships.

All research involving animal subjects at OHSU must be reviewed and approved by the university's?Institutional Animal Care and Use Committee (IACUC). The IACUC's priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. No live animal work may be conducted at OHSU without IACUC approval.

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Monkeypox viruses relatively stable on surfaces

The virus remains infectious on steel surfaces for up to 30 days, but can be effectively inactivated by alcohol-based disinfectants.

Smallpox viruses are notorious for their ability to remain infectious in the environment for a very long time. A study conducted by the Department of Molecular and Medical Virology at Ruhr University Bochum, Germany, has shown that temperature is a major factor in this process: at room temperature, a monkeypox virus that is capable of replicating can survive on a stainless steel surface for up to eleven days, and at four degrees Celsius for up to a month. Consequently, it's very important to disinfect surfaces. According to the study, alcohol-based disinfectants are very effective against monkeypox viruses, whereas hydrogen peroxide-based disinfectants have proved inadequate. The team published their findings in the Journal of Infectious Diseases on 2 May 2023.

Weeks of monitoring

Since 2022, the monkeypox virus has been transmitted more and more frequently from one human host to another. Although infections primarily result from direct physical contact, it's also possible to contract the virus through contaminated surfaces, for example in the household or in hospital rooms. "Smallpox viruses are notorious for their ability to remain infectious in the environment for a very long time," explains Dr. Toni Meister from the Department for Molecular and Medical Virology at Ruhr University Bochum. "For monkeypox, however, we didn't know the exact time frames until now."

The researchers therefore studied them by applying the virus to sanitised stainless steel plates and storing them at different temperatures: at four degrees, at 22 degrees, which roughly corresponds to room temperature, and at 37 degrees. They determined the amount of infectious virus after different periods of time, ranging from 15 minutes to several days to weeks.

Viruses remain infectious for a long time

Regardless of the temperature, there was little change in the amount of infectious virus during the first few days. At 22 and 37 degrees, the virus concentration dropped significantly only after five days. At 37 degrees, no virus capable of reproducing was detected after six to seven days, at 22 degrees it took ten to eleven days until infection was no longer possible. At four degrees, the amount of virus only dropped sharply after 20 days, and after 30 days there was no longer any danger of infection. "This is consistent with our experience that people can still contract monkeypox from surfaces in the household after almost two weeks," points out Professor Eike Steinmann, Head of the Department for Molecular and Medical Virology.

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Viruses could reshuffle the carbon cycle in a warming world

Microbes play important roles in ecosystems, and these roles are changing with global warming. Scientists also now know that most types of microbes are infected by viruses, but they know relatively little about how these viral infections could change how microbes react to warming. In this study, scientists describe many different ways that increasing temperatures could affect viruses and their microbial hosts. These changes could ultimately affect the responses of whole ecosystems to warming. The work exposes several important gaps in researchers' current knowledge about the connections between viruses, warming, and ecosystem functioning. Filling these gaps is crucial for understanding and predicting the effects of climate change on ecosystems.

This study creates a roadmap for understanding the many different ways that viruses could modify the effects of warming on communities of microbes. Viruses likely have strong effects on processes with microbes and the ways ecosystems function. Incorporating these previously ignored effects into ecosystem models will help scientists improve their predictions of how ecosystems could respond to climate change.

Microorganisms play integral roles in ecosystems by controlling the flow of energy and matter through processes like photosynthesis (carbon uptake), respiration (carbon release), and decomposition (carbon recycling). Climate change is currently altering how ecosystems function by changing how organisms operate within microbial food webs. Scientists know that viruses can have strong impacts on microbial processes, but they have less knowledge of how these impacts will change with future warming.

In this study, scientists from Duke University, the University of Tennessee Knoxville, the Netherlands Institute of Ecology, and Oak Ridge National Laboratory reviewed the potential impacts of warming on viruses and how these might alter scientific understanding of ecosystem responses to climate change. Warming likely affects several different stages of the viral infection cycle, as well as virus-host dynamics. However, there are still many gaps in our understanding about these effects. Because viruses are ubiquitous across all habitats and have strong effects on microbial functioning, filling these gaps is critical to understanding how warming will affect the flow of energy and matter within ecosystems. The researchers' preliminary models show that viruses could potentially tip the scales on natural carbon balances, causing some ecosystems to switch from being net carbon sources (releasing more carbon than they store) to being net carbon sinks (absorbing carbon). This study shows how incorporating viruses into predictive models can lead to new and unexpected effects on ecosystems in response to climate change.

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Scientists present evidence for a billion-years arms race between viruses and their hosts

Researchers have proposed a new evolutionary model for the origin of a kingdom of viruses called Bamfordvirae, suggesting a billion-years evolutionary arms race between two groups within this kingdom and their hosts.

Their study, published today as a Reviewed Preprint in eLife, provides what the editors say are convincing analyses that advance our understanding of the deep evolutionary history of viruses, the interaction between viruses and the first eukaryotes (organisms with cells that include a nucleus), and the diversification of viral lineages.

Viruses in the kingdom Bamfordvirae make up one of the most diverse groups that infect living organisms. They include the Nucleocytoplasmic Large DNA viruses (NCLDVs; the largest viruses characterised to date), virophages (viral parasites of other viruses), adenoviruses (common viruses that cause cold and flu-like symptoms), and Mavericks and Polinton-like viruses (both virus-like mobile genetic elements that colonise the genomes of their hosts).

There are two main hypotheses for the origins of these viruses: the 'nuclear-escape' and 'virophage-first' hypotheses. The nuclear-escape hypothesis says that a Maverick-like ancestor originated with hosts (endogenous), escaped from the host cell nucleus and gave rise to adenoviruses and NCLDVs. In contrast, the virophage-first hypothesis suggests that NCLDVs co-evolved with early virophages. Mavericks then evolved from virophages that became endogenous, with adenoviruses escaping from the host nucleus at a later stage.

"Despite these proposed scenarios, the diversification of viruses in the Bamfordvirae kingdom remains a major open question in virus evolution. To gain a better understanding of their history, we wanted to test the predictions made by both the nuclear-escape and virophage-first models, and consider alternative scenarios regarding the origin of different lineages," says José Gabriel Niño Barreat, Postdoctoral Research Assistant at the University of Oxford, UK. Barreat is a co-author of the study alongside Aris Katzourakis, Professor of Evolution and Genomics at the University of Oxford's Department of Biology.

Barreat and Katzourakis used two hypothesis-testing methods (maximum-likelihood and Bayesian frameworks) to compare the plausibility of the nuclear-escape versus alternative evolutionary scenarios. They focused on four key proteins shared by viruses in this lineage which are involved in the formation of viral capsids: major and minor capsid proteins, DNA-packaging ATPase, and protease. They applied another two methods that use genetic data to estimate rooted phylogenies, to infer the evolutionary trajectory of the different lineages. Then, they assessed whether adenoviruses and NCLDVs descended from a common ancestor, as predicted by the nuclear-escape scenario.

Their analyses revealed strong evidence against a sister relationship between adenoviruses and NCLDVs, as suggested by the nuclear-escape hypothesis. Instead, the findings suggest that adenoviruses descended from a common ancestor with Mavericks, to the exclusion of NCLDVs. At odds with a virophage-first scenario, the researchers found that the most recent common ancestor of Mavericks and adenoviruses was not a virophage. However, their work does not rule out the virophage-first hypothesis completely, making it the one best supported by current phylogenetic analyses.

Additionally, their work provides support for the positioning of the Bamfordvirae ancestral root between virophages and the other viral lineages. This positioning pointed the team towards a new model for the evolutionary origins of these viruses.

"The model proposes that the Bamfordvirae ancestor did not originate from an invasion of the eukaryotic cell nucleus, and that it was a non-virophage DNA virus with a small genome," says co-author Aris Katzourakis. "The lifestyle of virophages would have evolved at a later stage as these became specialised parasites of the ancestral NCLDVs." Katzourakis adds that the relative timing of events suggests the most recent common ancestor of the Bamfordvirae kingdom existed more than a billion years ago, extending to the initial stages of eukaryotic life. However, an absolute timescale for the precise dating of these events is not currently available.

Another limitation of the study is that the phylogenetic signal in the protein data analysed may have been obscured by the deep divergences and extreme diversity in this lineage. However, the authors were able to robustly distinguish between alternative scenarios, and the focus on the origin and development of the viral capsid provides a simple way to explain the available data.

"This work contributes to our knowledge on how viruses evolve different evolutionary strategies, for example to become parasites of other viruses like virophages, or viral giants like NCLDVs," Barreat says. "As well as playing important roles in Earth's ecosystems, it is becoming increasingly clear that viruses may have contributed to major evolutionary transitions during the history of life. Therefore, understanding the deep evolutionary history of viruses provides more context for these ancient interactions and the actors involved."

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