New roadmap to prevent pandemics centers on protecting biodiversity

An international team of 25 scientists has proposed a roadmap for how to prevent the next pandemic by conserving natural areas and promoting biodiversity, thereby providing animals with enough food, safe havens and distance to limit contact and the transfer of pathogens to humans.

Pandemics begin when disease-harboring animals, such as bats, come in close proximity with people, livestock or other animals and pass on new pathogens.

Viruses such as SARS-CoV-2, SARS-CoV-1, Nipah, Hendra and possibly Ebola have all fatally spilled over from bats to humans, sometimes through an intermediate host.

"The world is focused on how can we detect and then contain a novel pathogen once it is circulating in humans, rather than how can we prevent that pathogen from entering the human population in the first place," said Raina Plowright, professor in the Department of Public and Ecosystem Health at Cornell University, and first author of the paper, "Ecological Countermeasures to Prevent Pathogen Spillover and Subsequent Pandemics," published in Nature Communications.

The pandemic-prevention strategy is based on insights from a pair of 2022 papers that serve as a case study applicable to all animals that potentially carry zoonotic diseases.

Those papers -- about how bats can spread fatal Hendra virus to horses and people -- explained that when bats lose their natural habitats and winter food sources, their large populations splinter and they migrate in small groups to agricultural and urban areas.

They also become stressed, partly due to inadequate food sources, and they shed more virus in their urine.

The virus falls to the ground where grazing horses become infected; horses in turn can then infect people.

But when natural habitats can provide adequate food, especially in fallow winter months, the bats return to these habitats, aggregate in large numbers, and stop shedding virus.

The roadmap uses this and other case studies to explain the mechanisms linking environmental change and spillover of pathogens from animals to humans, and identifies ecological interventions to disrupt these links and policy frameworks to implement them.

Ecological interventions begin by protecting the places where animals eat.

"We need to make sure there's always an abundant supply of food available at all times of year, especially when animals are in stressful life history stages like reproduction and migration," Plowright said.

Next, it's important to protect where animals may roost or aggregate, as tens of thousands of bats can roost in canopies and caves, so when these areas are disturbed, these populations can splinter, move and shed more virus.

Also, cave dwelling bats may not have other caves to move to, in which case they stay put, become more stressed and likely shed more virus.

Protecting lands that act as buffers between people and wildlife is also key.

"There are trillions of microbes in nature, but we rarely actually get sick, because there are many, many barriers between us and new pathogens," Plowright said.

Lastly, for communities who come in contact with animals, it's important to ensure people have the protection that they need to avoid pathogen exposure, Plowright said.

The study's authors emphasize the need for an international agency or panel that can assess and synthesize data on pandemic prevention, preparedness and response and collect metrics on intactness of landscapes, ecological integrity and biodiversity.

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Candida evolution disclosed: New insights into fungal infections

Global fungal infections, which affect one billion people and cause 1.5 million deaths each year, are on the rise due to the increasing number of medical treatments that heighten vulnerability. Patients undergoing chemotherapy or immunosuppressive treatments after organ transplant often present compromised immune systems. Given the emergence of resistant strains, the limited variety of current antifungal drugs as well as their cost and side effects, the treatment of these infections is challenging and brings about an urgent need for more effective treatments.

In this context, a team from the Institute for Research in Biomedicine (IRB Barcelona) and the Barcelona Supercomputing Center -- Centro Nacional de Supercomputación (BSC-CNS), led by the ICREA researcher Dr. Toni Gabaldón, has identified hundreds of genes subject to recent, clinically-relevant selection in six species of the fungal pathogen Candida.

"This work highlights how thesepathogens adapted to humans and antifungal drugs and provides valuable knowledge that could lead to better treatments for Candida infections," explains Dr. Gabaldón, head of the Comparative Genomics lab at IRB Barcelona and the BSC.

More than 2,000 genomes from 6 different species

The study delves into the evolutionary landscape of Candida pathogens by analysing approximately 2,000 genomes from clinical samples of six major Candida species.

These genomes are stored in public databases. The researchers compared these genomes to a reference, creating a comprehensive catalogue of genetic variants.

Building on previous work addressing drug-resistant strains, the researchers conducted a Genome-Wide Association Study (GWAS) to identify genetic variants linked to antifungal drug resistance in clinical isolates.

This approach provided insights into both known and novel mechanisms of resistance towards seven antifungal drugs in three Candida species.

"Additionally, a concerning finding has arisen from the study: the potential spread of resistance through mating between susceptible and resistant strains, contributing to the prevalence of drug-resistant Candida pathogens," explains Dr. Miquel Àngel Schikora-Tamarit, a postdoctoral researcher in the same lab and first author of the study.

In addition, by focusing on variants acquired recently among clinical strains, the researches detected shared and species-specific genetic signatures of recent selection that inform on which adaptations might be needed to thrive and spread in human-related environments.

Beyond the novel insights into the adaptation of Candida, the study provides a valuable resource, namely a comprehensive catalogue of variants, selection signatures, and drivers of drug resistance.

This knowledge not only contributes to our understanding of these infections but also lays the groundwork for future experiments and potential advancements in the development of more effective treatments for Candida infections.

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Mysterious family of microbial proteins hijack crops' cellular plumbing

Many of the bacteria that ravage crops and threaten our food supply use a common strategy to cause disease: they inject a cocktail of harmful proteins directly into the plant's cells.

For 25 years, biologist Sheng-Yang He and his senior research associate Kinya Nomura have been puzzling over this set of molecules that plant pathogens use to cause diseases in hundreds of crops worldwide ranging from rice to apple trees.

Now, thanks to a team effort between three collaborating research groups, they may finally have an answer to how these molecules make plants sick -- and a way to disarm them.

The findings appear Sept. 13 in the journal Nature.

Researchers in the He lab study key ingredients in this deadly cocktail, a family of injected proteins called AvrE/DspE, that cause diseases ranging from brown spot in beans and bacterial speck in tomatoes to fire blight in fruit trees.

Ever since their discovery in the early 1990s, this family of proteins has been of great interest to those who study plant disease. They are key weapons in the bacterial arsenal; knocking them out in a lab renders otherwise-dangerous bacteria harmless. But, despite decades of effort, many questions about how they work remain unanswered.

Researchers had identified a number of proteins in the AvrE/DspE family that suppressed the plant's immune system, or that caused dark water-soaked spots on a plant's leaves -- the first telltale signs of infection. They even knew the underlying sequence of amino acids that linked to form the proteins, like beads on a string. But they didn't know how this string of amino acids folded into a 3D shape, so they couldn't easily explain how they worked.

Part of the problem is that the proteins in this family are huge. Whereas an average bacterial protein might be 300 amino acids long; AvrE/DspE-family proteins are 2000.

Researchers have looked for other proteins with similar sequences for clues, but none with any known functions showed up.

"They're weird proteins," He said.

So they turned to a computer program released in 2021 called AlphaFold2, which uses artificial intelligence to predict what 3D shape a given string of amino acids will take.

The researchers knew that some members of this family help the bacteria evade the plant's immune system. But their first glimpse of the proteins' 3D structure suggested an additional role.

"When we first saw the model, it was nothing like what we had thought," said study co-author Pei Zhou, a professor of biochemistry at Duke whose lab contributed to the findings.

The researchers looked at AI predictions for bacterial proteins that infect crops including pears, apples, tomatoes and corn, and they all pointed to a similar 3D structure. They appeared to fold into a tiny mushroom with a cylindrical stem, like a straw.

The predicted shape matched up well with images of a bacterial protein that causes fire blight disease in fruit trees that was captured using a cryo-electron microscope. From the top down, this protein looked very much like a hollow tube.

Which got the researchers thinking: Perhaps bacteria use these proteins to punch a hole in the plant cell membrane, to "force the host for a drink" during infection, He said.

Once bacteria enter the leaves, one of the first areas they come across is a space between cells called the apoplast. Normally, plants keep this area dry to enable gas exchange for photosynthesis. But when bacteria invade, the inside of the leaf becomes waterlogged, creating a moist cozy haven for them to feed and multiply.

Further examination of the predicted 3D model for the fire blight protein revealed that, while the outside of the straw-like structure is water-resistant, its hollow inner core has a special affinity for water.

To test the water channel hypothesis, the team joined forces with Duke biology professor Ke Dong and co-first-author Felipe Andreazza, a postdoctoral associate in her lab. They added the gene readouts for the bacterial proteins AvrE and DspE to frog eggs, using the eggs as cellular factories for making the proteins. The eggs, placed in a dilute saline solution, quickly swelled and burst with too much water.

The researchers also tried to see if they could disarm these bacterial proteins by blocking their channels. Nomura focused on a class of tiny spherical nanoparticles called PAMAM dendrimers. Used for more than two decades in drug delivery, these dendrimers can be made with precise diameters in a lab.

"We were tinkering with the hypothesis that if we found the right diameter chemical, maybe we could block the pore," He said.

After testing different sized particles, they identified one they thought might be just the right size for jamming the water channel protein produced by the fire blight pathogen, Erwinia amylovora.

They took frog eggs engineered to synthesize this protein and doused them with the PAMAM nanoparticles, and water stopped flowing into the eggs. They didn't swell.

They also treated Arabidopsis plants infected with the pathogen Pseudomonas syringae, which causes bacterial speck. The channel-blocking nanoparticles prevented the bacteria from taking hold, reducing pathogen concentrations in the plants' leaves by 100-fold.

The compounds were effective against other bacterial infections too. The researchers did the same thing with pear fruits exposed to the bacteria that cause fire blight disease, and the fruits never developed symptoms -- the bacteria didn't make them sick.

"It was a long shot, but it worked," He said. "We're excited about this."

The findings could offer a new line of attack against many plant diseases, the researchers said.

Plants produce 80% of the food we eat. And yet more than 10% of global food production -- crops such as wheat, rice, maize, potato and soybean -- are lost to plant pathogens and pests each year, costing the global economy a whopping $220 billion.

The team has filed a provisional patent on the approach.

The next step, said Zhou and co-first-author Jie Cheng, a Ph.D. student in Zhou's lab, is to figure out how this protection works, by getting a more detailed look at how the channel-blocking nanoparticles and the channel proteins interact.

"If we can image those structures we can have a better understanding and come up with better designs for crop protection," Zhou said.

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'Time-traveling' pathogens in melting permafrost pose likely risk to environment

Ancient pathogens that escape from melting permafrost have real potential to damage microbial communities and might potentially threaten human health, according to a new study by Giovanni Strona of the European Commission Joint Research Centre and colleagues, published July 27 in the open-access journal PLOS Computational Biology.

The idea that "time-traveling" pathogens trapped in ice or hidden in remote laboratory facilities could break free to cause catastrophic outbreaks has inspired generations of novelists and screenwriters. While melting glaciers and permafrost are giving many types of dormant microbes the opportunity to re-emerge, the potential threats to human health and the environment posed by these microbes have been difficult to estimate.

In a new study, Strona's team quantified the ecological risks posed by these microbes using computer simulations. The researchers performed artificial evolution experiments where digital virus-like pathogens from the past invade communities of bacteria-like hosts. They compared the effects of invading pathogens on the diversity of host bacteria to diversity in control communities where no invasion occurred.

The team found that in their simulations, the ancient invading pathogens could often survive and evolve in the modern community, and about 3 percent became dominant. While most of the dominant invaders had little effect on the composition of the larger community, about 1 percent of the invaders yielded unpredictable results. Some caused up to one third of the host species to die out, while others increased diversity by up to 12 percent compared to the control simulations.

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Using paleogenomics to elucidate 10,000 years of immune system evolution

Scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France have used paleogenomics to trace 10,000 years of human immune system evolution. They analyzed the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia. They were able to date the increase in frequency of most of the mutations that are advantageous in defending against pathogens to after the Bronze Age, 4,500 years ago. The scientists also observed that mutations conferring a higher risk of developing inflammatory disorders have become more frequent over the past 10,000 years. These enlightening results on the effects of natural selection on immunity genes were published in the journal Cell Genomics on January 13, 2023.

In the 1950s, the geneticist J.B.S. Haldane attributed the maintenance or persistence of the mutation responsible for anomalies in red blood cells commonly observed in Africa to the protection these anomalies provided against malaria, an endemic infection that claims millions of lives. This theory suggested that pathogens are among the strongest selective pressures faced by humans. Several population genetics studies subsequently confirmed the theory. But major questions remained, especially regarding the specific epochs during which the selective pressures exerted by pathogens on human populations were strongest and their impact on the present-day risk of developing inflammatory or autoimmune disorders.

To address these questions, scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France, in collaboration with the Imagine Institute and The Rockefeller University (United States), adopted an approach based on paleogenomics. This discipline, which studies the DNA from fossil remains, has led to major discoveries about the history and evolution of humans and human diseases, as illustrated by the decision to award the 2022 Nobel Prize in Physiology or Medicine to the paleogeneticist Svante Pääbo. In the study led by the Institut Pasteur, published on January 13 in the journal Cell Genomics, the scientists analyzed the variability of the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia -- a period covering the Neolithic, the Bronze Age, the Iron Age, the Middle Ages and the present.

By reconstituting the evolution over time of hundreds of thousands of genetic mutations, the scientists initially identified mutations that rapidly increased in frequency in Europe, indicating that they were advantageous. These mutations that evolved under "positive" natural selection are mainly located in 89 genes enriched in functions relating to the innate immune response, including especially the OAS genes -- which are responsible for antiviral activity -- and the gene responsible for the ABO blood group system. Surprisingly, most of these positive selection events, which demonstrate a genetic adaptation to the pathogenic environment, began recently, from the start of the Bronze Age, around 4,500 years ago. The scientists explain this "acceleration" in adaptation by the growth in the human population during this period and/or by strong selective pressures exerted by pathogens in the Bronze Age, probably linked to the spread of severe infectious diseases such as plague.

At the same time, the scientists also looked at the opposite situation, in other words, mutations whose frequency fell significantly over the past ten millennia. These mutations are probably subject to "negative" selection because they increase the risk of disease. They noted that once again, these selection events mainly began in the Bronze Age. Many of these disadvantageous mutations were also located in genes associated with the innate immune response, such as TYK2, LPB, TLR3 and IL23R, and have been confirmed in experimental research to have a deleterious effect in terms of infectious disease risk. The results emphasize the value of adopting an evolutionary approach in research on genetic susceptibility to infectious diseases.

Finally, the scientists explored the theory that the selection exerted by pathogens in the past gave an advantage to alleles conferring resistance to infectious diseases, but that in turn these alleles have increased the present-day risk of autoimmune or inflammatory disorders. They investigated the few thousand mutations known to increase susceptibility firstly to tuberculosis, hepatitis, HIV or COVID-19, and secondly to rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease. By looking at the evolution of these mutations over time, they observed that those associated with an increased risk of inflammatory disorders -- including Crohn's disease -- became more frequent over the past 10,000 years, while the frequency of those associated with a risk of developing infectious diseases decreased. "These results suggest that the risk of inflammatory disorders has increased in Europeans since the Neolithic period because of a positive selection of mutations improving resistance to infectious diseases," explains Lluis Quintana-Murci, director of the study and Head of the Human Evolutionary Genetics Unit (Institut Pasteur/CNRS Evolutionary Genomics, Modeling and Health Unit/Université Paris Cité).

The results of the study, which harnessed the huge potential of paleogenomics, show that natural selection has targeted human immunity genes over the past ten millennia in Europe, especially since the start of the Bronze Age, and contributed to present-day disparities in terms of the risk of infectious and inflammatory diseases.

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Study demonstrates that ticks weaken skin's immune response

Hitherto, scientists have not fully understood why ticks are such dangerous disease vectors. A research team led by Johanna Strobl and Georg Stary from MedUni Vienna's Department of Dermatology shows that tick saliva inhibits the skin's defence function, thereby increasing the risk of diseases such as tick-borne encephalitis (TBE) or Lyme disease. The study was recently published in the Journal of Clinical Investigation.

The researchers carried out their investigations on skin samples from volunteers and also on models of human skin, mimicking the bite of the most common European tick (Ixodes ricinus). In both cases, the team led by Georg Stary (MedUni Vienna's Department of Dermatology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases) in collaboration with the research group of Hannes Stockinger (Center for Pathophysiology, Infectiology and Immunology at MedUni Vienna) identified rapidly occurring patterns of immunomodulation. For example, it was found that the function of immune cells, especially T cells, which are important for immunological memory, was disrupted by contact with tick saliva.

Tick saliva modulates immune system

The scientists made similar observations in early stages of model infection by Borrelia burgdorferi, the most common cause of Lyme disease. They found that pre-incubation of Lyme disease-transmitting bacteria (B. burgdorferi spirochetes) with tick salivary gland extracts impedes the accumulation of immune cells in the skin and increases the pathogen burden. "Overall, we found that tick feeding causes profound changes in the skin's immune system inhibiting the local immune response. This means that dangerous pathogens that are introduced into the skin together with tick saliva, can multiply more easily, leading to infection," says Johanna Strobl, lead author of the study, summarising the main research findings.

Climate change increases danger from ticks

Austria is one of the countries with the greatest prevalence of ticks. Nearly every second European tick is infected with pathogens, Lyme disease and tick-borne encephalitis (TBE) being the most common tick-borne diseases. The arachnids become active at a temperature of seven degrees. Due to rising temperatures associated with climate change, ticks now also pose a threat in higher-altitude regions of Austria and well into late autumn.

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Synapse-related genes in microglia are changed by contextual fear conditioning

Microglia acts as the first line of defense in the central nervous system, constantly scanning for pathogens and abnormalities and releasing small proteins called cytokines to help wade off infections. Previous research has shown that, in mice conditioned to fear a particular environment (contextual fear conditioning), microglia play a pivotal role in transferring traumatic memories from short to long-term memory (fear memory consolidation), and the memories subsequent extinction.

Now, Tohoku University scientists have demonstrated that microglial genes associated with the synapse -- structures that allow neurons to pass signals to one another -- undergo changes in response to the consolidation and extinction of contextual fear conditioning. This suggests that microglia and neurons crosstalk via 'non-immune' functions and clarifies the mechanisms linking microglia and neuronal activity related to fear conditioning.

Details of their research were published in the journal Brain Research Bulletin on August 18, 2022.

Dr Zhiqian Yu and Professor Hiroaki Tomita from Tohoku University's Graduate School of Medicine and their team has previously revealed that when mice were subjected to chronic and acute stress, their microglial released a type of cytokine known as TNF-a, which is used by the immune system for cell signaling. TNF-a increased during fear memory consolidation, but returned to base levels after extinction. Hippocampal TNF-a, furthermore, blocks the retrieval and reconsolidating of contextual fear and spatial memories.

Building on the previous study, the team adopted microarray techniques in microglia from mice exposed to contextual fear conditioning. They showed that synapse-related genes in microglia are changed by contextual fear conditioning. However, they also discovered that consolidating the fear memory induced immune dysfunction in microglia and did not recover even during the process of extinction.

Within the microglia's plethora of synaptic function-related genes, Gamma-aminobutyric acid (GABA) and GABAR receptors (GABAR) are the earliest neurotransmitter systems to emerge during development. The GABARB3 encodes the ?3 subunit of GABAA receptors in neurological disorders such as epilepsy and autism.

"Using real-time PCR and immune stain technologies, we found that GABRB3 was expressed in microglial cytoplasm and the long branching processes of the hippocampus," said Yu. "The mRNA and protein levels of GABRB3 changed significantly after fear memory consolidation but recovered after extinction."

Additionally, the researchers investigated a family of proteins called Synapsin, which regulate neurotransmitters' release at the synapse. The transcription of microglial Synapsin was expressed in MG-6 cell line and primary microglia that increased under fear memory consolidation but recovered after fear memory extinction.

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Road signs for immune defense cells

Organisms are constantly invaded by pathogens such as viruses. Our immune system swings into action to combat these pathogens immediately. The innate non-specific immune response is triggered first, and the adaptive or acquired immune response follows. In this second defence reaction, specialised cytotoxic T lymphocytes known as killer T cells destroy cells in the body that have been infected and thus prevent damage from spreading. Humans possess a repertoire of some 20 million T cell clones with varying specificity to counter the multitude of infectious agents that exist. But how do the killer T cells know where danger is coming from? How do they recognise that something is wrong inside a cell in which viruses are lurking? They can't just have a quick peek inside.

At this point, antigen processing comes into play. The process can be compared to making a road sign. The molecular barcode is "processed" or assembled in the cell -- in the endoplasmic reticulum, to be exact. Special molecules are used in its making, the MHC class I molecules. They are loaded with information about the virus invader in a molecular machine, the peptide loading complex (PLC). This information consists of peptides, fragments of the protein foreign to the body. These fragments also contain epitopes, the molecular segments that elicit a specific immune response. During the loading process, an MHC I-peptide epitope complex thus forms, and this is the road sign that is then transported to the surface of the cell and presented in a readily accessible form to the killer T cells -- we could almost say that it is handed to them on a silver platter. The chaperones, special accessory proteins that assist the correct folding of proteins with complex structures in cells, also play a significant role.

The chaperones that support antigen processing are calreticulin, ERp57, and tapasin. But how do they work together? And how important are they for antigen processing? An answer has now been supplied by a study carried out by Goethe University Frankfurt and the University of Oxford and published in Nature Communications. "With this study, we have achieved a breakthrough in our understanding of cellular quality control," says Professor Robert Tampé, Director of the Institute of Biochemistry at Goethe University Frankfurt. He explains the logic underlying this quality control process as follows: "The MHC I-peptide epitope complex, the road sign, needs to be exceptionally stable, and for quite a long time, because the adaptive immune response does not start instantly. It needs 3 to 5 days to get going." So, the sign must not collapse after one day; that would be disastrous, as the immune defence cells would then fail to detect cells infected by a virus. This would mean that they would not destroy these cells and the virus would be able to continue its spread unhindered. A similar problem would arise if a cell in the body had mutated into a tumour cell: the threat would remain undetected. It is imperative, therefore, that a quality control system is in place.

As the study shows, the chaperones are central process components: they give the road sign the long-term stability it must have by making a strict selection. By rejecting the short-lived virus fragments in the mass of available material, they ensure that only MHC I molecules loaded with the best and most stable peptide epitopes in complex with MHC I are released from the peptide loading complex. The chaperones have different tasks in this selection process that is so important for the adaptive immune response, Tampé says: "Tapasin acts as a catalyst that accelerates the exchange of suboptimal peptide epitopes for optimal epitopes. Calreticulin and ERp57, in contrast, are deployed universally." This concerted approach ensures that only stable MHC I complexes with optimal peptide epitopes reach the cell surface and perform their role of guiding the killer T cells to the infected or mutated cell.

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Impact of climate change on human pathogenic diseases subject of new study by UH researchers

A comprehensive assessment of scientific literature has uncovered empirical evidence that more than 58% of human diseases caused by pathogens, such as dengue, hepatitis, pneumonia, malaria, Zika and more, have been -- at some point -- aggravated by climatic hazards. That eye-opening and startling finding is the topic of a research paper published on August 8 in Nature Climate Change by a team of researchers from the University of Hawaii at Manoa.

The researchers carried out a systemic search for empirical examples about the impacts of 10 climatic hazards sensitive to greenhouse gas (GHG) emissions on each known human pathogenic disease. These hazards included warming, drought, heatwaves, wildfires, extreme precipitation, floods, storms, sea level rise, ocean biogeochemical change, and land cover change.

Combining two authoritative lists of all known infections and pathogenic diseases that have affected humanity in recorded history, researchers then reviewed more than 70,000 scientific papers for empirical examples about each possible combination of a climatic hazard impacting each of the known diseases.

The research revealed that warming, precipitation, floods, drought, storm, land cover change, ocean climate change, fires, heatwaves and sea level changes were all found to influence diseases triggered by viruses, bacteria, animals, fungi, protozoans, plants and chromists. Pathogenic diseases were primarily transmitted by vectors, although case examples were also found for waterborne, airborne, direct contact and foodborne transmission pathways. Ultimately, the research found that more than 58%, or 218 out of 375, of known human pathogenic diseases had been affected at some point, by at least one climatic hazard, via 1,006 unique pathways.

"Given the extensive and pervasive consequences of the COVID 19 pandemic, it was truly scary to discover the massive health vulnerability resulting as a consequence of greenhouse gas emissions," said Camilo Mora, geography professor in the College of Social Sciences (CSS) and lead author of the study. "There are just too many diseases, and pathways of transmission, for us to think that we can truly adapt to climate change. It highlights the urgent need to reduce greenhouse gas emissions globally."

An interactive web-page showing each connection between a climatic hazard and a disease case was developed by the research team. The tool allows users to query specific hazards, pathways and disease groups, and see the available evidence.

The UH Manoa research team included experts from CSS, Department of Earth Sciences in the School of Ocean and Earth Science and Technology, Marine Biology Graduate Program in the School of Life Sciences, Department of Natural Resources and Environmental Management in the College of Tropical Agriculture and Human Resources, and Hawaii Institute of Marine Biology in SOEST.

Other key findings include:

•     Climatic hazards are bringing pathogens closer to people. Numerous climatic hazards are increasing the area and duration of environmental suitability facilitating the spatial and temporal expansion of vectors and pathogens. Warming and precipitation changes, for instance, were associated with range expansion of vectors such as mosquitoes, ticks, fleas, birds and several mammals implicated in outbreaks by viruses, bacteria, animals and protozoans, including dengue, chikungunya, plague, Lyme disease, West Nile virus, Zika, trypanosomiasis, echinococcosis and malaria to name a few.
•     Climatic hazards are bringing people closer to pathogens. Climatic hazards were also implicated with the forced displacement and migration of people causing or increasing new contacts with pathogens. Heatwaves, for instance, have been associated with rising cases of several waterborne diseases such as Vibrio (a kind of bacteria)-associated infections, primary amoebic meningoencephalitis and gastroenteritis. Storms, floods and sea level rise caused human displacements implicated in cases of leptospirosis, cryptosporidiosis, Lassa fever, giardiasis, gastroenteritis, Legionnaires' diseases, cholera, salmonellosis, shigellosis, pneumonia, typhoid, hepatitis, respiratory disease and skin diseases among others.
•     Climatic hazards have enhanced specific aspects of pathogens, including improved climate suitability for reproduction, acceleration of the life cycle, increasing seasons/length of likely exposure, enhancing pathogen vector interactions (for example, by shortening incubations) and increased virulence. For instance, storms, heavy rainfall and floods created stagnant water, increasing breeding and growing grounds for mosquitoes and the array of pathogens that they transmit (for example, leishmaniasis, malaria, Rift Valley fever, yellow fever, St. Louis encephalitis, dengue and West Nile fever). Climatic hazards were also implicated in the increasing capacity of pathogens to cause more severe illness. For example, heatwaves were suggested as a natural selective pressure toward "heat resistant" viruses, whose spillover into human populations results in increased virulence as viruses can better cope with the human body's main defense, which is fever.
•     Climatic hazards have also diminished human capacity to cope with pathogens by altering body condition; adding stress from exposure to hazardous conditions; forcing people into unsafe conditions; and damaging infrastructure, forcing exposure to pathogens and/or reducing access to medical care. Drought, for instance, was conducive to poor sanitation responsible for cases of trachoma, chlamydia, cholera, conjunctivitis, Cryptosporidium, diarrheal diseases, dysentery, Escherichia coli, Giardia, Salmonella, scabies and typhoid fever.

Researchers also found that, while the great majority of diseases were aggravated by climatic hazards, some were diminished (63 out of 286 diseases). Warming, for example, appears to have reduced the spread of viral diseases probably related to unsuitable conditions for the virus or because of a stronger immune system in warmer conditions. However, most diseases that were diminished by at least one hazard were at times aggravated by another and sometimes even the same hazard.

Read more at Science Daily

How the intestine replaces and repairs itself

To act as a robust barrier against pathogens while also absorbing needed nutrients, the lining of the intestines must regenerate on a daily basis to remain equal to the task. The intestine's resident stem cells are responsible for meeting this need for constant repair and replenishment, but each stem cell faces decisions that depend on the overall conditions of the intestine and the needs of the moment. Bad decisions and poor coordination could result in intestinal diseases or cancer.

A new study suggests that stem cells are able to integrate cues from their surroundings and coordinate their behavior across the tissue through networks of vasculature in their close vicinity.

Rockefeller scientists found that lymphatic capillaries -- fine vessels that transport immune cells and drain fluids from tissues -- represent a signaling hub that communicates with stem cells to regulate their activity. With molecular guidance from the lymphatics, the stem cells produce daughter cells to repopulate the intestinal lining or self-renew to restock the stem cell reserve.

The findings, published in the journal Cell Stem Cell, provide new insights about primary intestinal components whose disrupted communication may contribute to intestinal disorders, such as inflammatory bowel disease. "The key to treating these diseases will be to figure out who talks to whom in this ecosystem and how we can reset the communication networks," says Rachel Niec, a clinical scholar in the laboratory of Elaine Fuchs.

Communications in the crypt

The intestinal stem cells reside in so-called crypts, found at the base of densely packed indentations in the intestinal lining. The stem cells may renew and stay in the crypt, or differentiate into specialized cells, which then migrate out of the crypt to replenish the gut lining. "To understand how stem cells balance self-renewal with differentiation, we needed a more complete picture of crypt niches," says Marina Schernthanner, a graduate student in the Fuchs lab.

To zoom in on the crypt, the team used a suite of techniques, including single-cell and spatial transcriptomics, which allowed them to identify cell types at specific locations and study their signaling molecules. The results showed that lymphatic capillaries, which form an intimate connection with the stem cells in the crypt, produce a number of proteins known to be important for stem cell functioning.

One previously underappreciated protein, REELIN, emerged as a top candidate for mediating communications between lymphatics and stem cells. By manipulating the amount of REELIN in lab-grown intestinal organoid cultures in some experiments and genetically suppressing it in mice in others, the researchers found that REELIN directly governs the regenerative behavior of intestinal stem cells.

The involvement of the lymphatic system in stem cell functioning is a relatively new concept. A previous study by the Fuchs team revealed that lymphatics are also closely involved with stem cells of the skin and play a key role in hair regeneration. There, however, it is the hair follicle stem cells that signal to lymphatic capillaries. By controlling their interactions with lymphatics, the stem cells synchronize hair regeneration across the tissue. "This suggests that lymphatics may be a conserved feature of stem cell niches, but their relationship to stem cells are likely tailored around the needs of each tissue," Niec says.

From Science Daily

Spaceflight: Microgravity analog culture profoundly affects microbial infection process in 3-D human tissue models

Infectious microbes have evolved sophisticated means to invade host cells, outwit the body's defenses and cause disease. While researchers have tried to puzzle out the complicated interactions between microorganisms and the host cells they infect, one facet of the disease process has often been overlooked -- the physical forces that impact host-pathogen interactions and disease outcomes.

In a new study, corresponding authors Cheryl Nickerson, Jennifer Barrila and their colleagues demonstrate that under low fluid shear force conditions that simulate those found in microgravity culture during spaceflight, the foodborne pathogen Salmonella infects 3-D models of human intestinal tissue at much higher levels, and induces unique alterations in gene expression.

This study advances previous work by the same team showing that physical forces of fluid shear acting on both the pathogen and host can transform the landscape of infection.

Understanding this subtle interplay of host and pathogen during infection is critical to ensuring astronaut health, particularly on extended space missions. Such research also sheds new light on the still largely mysterious processes of infection on earth, as low fluid shear forces are also found in certain tissues in our bodies that pathogens infect, including the intestinal tract.

While the team has extensively characterized the interaction between conventionally grown shake flask cultures of Salmonella Typhimurium and 3-D intestinal models, this study marks the first time that S. Typhimurium has been grown under the low fluid shear conditions of simulated microgravity and then used to infect a 3-D model of human intestinal epithelium co-cultured with macrophage immune cells, key cell types targeted by Salmonella during infection.

The 3-D co-culture intestinal model used in this study more faithfully replicates the structure and behavior of the same tissue within the human body and is more predictive of responses to infection, as compared with conventional laboratory cell cultures.

Results showed dramatic changes in gene expression of 3-D intestinal cells following infection with both wild-type and mutant S. Typhimurium strains grown under simulated microgravity conditions. Many of these changes occurred in genes known to be intimately involved with S. Typhimurium's prodigious ability to invade and colonize host cells and escape surveillance and destruction by the host's immune system.

"A major challenge limiting human exploration of space is the lack of a comprehensive understanding of the impact of space travel on crew health," Nickerson says. "This challenge will negatively impact both deep space exploration by professional astronauts, as well as civilians participating in the rapidly expanding commercial space market in low Earth orbit. Since microbes accompany humans wherever they travel and are essential for controlling the balance between health and disease, understanding the relationship between spaceflight, immune cell function, and microorganisms will be essential to understand infectious disease risk for humans."

Nickerson, who co-directed the new study with Jennifer Barrila, is a researcher in the Biodesign Center for Fundamental and Applied Microbiomics and is also a professor with ASU's School of Life Sciences. The research appears in the current issue of the journal Frontiers in Cellular and Infection Microbiology

Life-altering force

Life on earth has diversified into an almost incomprehensibly vast array of forms, evolving under wildly dissimilar environmental conditions. Yet one parameter has remained constant. Throughout the 3.7-billion-year history of life on earth, all living organisms evolved under, and respond to, the pull of Earth's gravity.

For more than 20 years, Nickerson has been a pioneer in exploring the effects of the reduced microgravity environment of spaceflight on a range of pathogenic microbes and the impact on interactions with human cells and animals they infect. She and her colleagues have doggedly pursued this research in both land-based and spaceflight settings, the results of which helped lay the foundation for the rapidly growing research field, mechanobiology of infectious disease, the study of how physical forces impact infection and disease outcomes.

Among their important findings is that the low fluid shear conditions associated with the reduced gravity environment of spaceflight and spaceflight analog culture are similar to those encountered by pathogens inside the infected host, and that these conditions can induce unique changes in the ability of pathogenic microbes like Salmonella to aggressively infect host cells and exacerbate disease, a property known as virulence.

The infectious agent explored in the new study, Salmonella Typhimurium, is a bacterial pathogen responsible for gastrointestinal disease in humans and animals. Salmonella is the leading cause of death from food-borne illness in the United States. According to the CDC, Salmonella bacteria cause about 1.35 million infections, 26,500 hospitalizations, and 420 deaths in the United States each year. Foods contaminated by the bacteria are the primary source for most of these illnesses.

Salmonella infection typically causes diarrhea, fever, and stomach cramps, beginning 6 hours to 6 days after infection. Illness from the disease usually lasts 4 to 7 days. In severe cases, hospitalization may be required.

'Shear' probability?

Cells in mammalian organisms, including humans, as well as the bacterial cells that infect them, are exposed to extracellular fluid flowing over their outer surfaces. Just as a gentle downstream current will affect the pebbles in the underlying streambed differently than a raging torrent, so the force of fluid gliding over cell surfaces can cause changes to affected cells. This liquid abrasion of cell surfaces is known as fluid shear.

Since spaceflight experiments are rare and access to the space research platform is currently limited, researchers often simulate the low fluid shear conditions that microbes encounter during culture in spaceflight by growing cells in liquid growth media within a device known as a rotating wall vessel bioreactor or RWV. As the cylindrical reactor rotates, cells are maintained in suspension, gently and continuously tumbling in their surrounding culture medium. This process mimics the low fluid shear conditions of microgravity that cells experience during culture in spaceflight.

The team has also shown that this fluid shear level is relevant to conditions that microbial cells encounter in the human intestine and other tissues during infection, triggering changes in gene expression that can help some pathogens better colonize host cells and evade the immune system's efforts to destroy them.

Portrait of an intruder

The study found significant changes in both gene expression and ability to infect 3-D intestinal models by Salmonella bacteria cultured in the RWV bioreactor. These experiments involved two S. Typhimurium strains, one unaltered or wild type strain and one mutant strain.

The mutant strain was otherwise identical to the wild type but lacked an important protein known as Hfq, a major stress response regulator in Salmonella. In earlier research, Nickerson and her team discovered that Hfq acts as a master regulator of Salmonella's infection process in both spaceflight and spaceflight analog culture. They later discovered additional pathogens that also use Hfq to regulate their responses to these same conditions.

Unexpectedly, in the current study, the hfq mutant strain was still able to attach, invade into, and survive within 3-D tissue models at levels comparable to the wild type strain. In agreement with this finding, many genes responsible for Salmonella's ability to colonize human cells, including those associated with cell adherence, motility, and invasion were still activated in the mutant strain under simulated microgravity conditions, despite the removal of Hfq.

From the host perspective, the 3-D intestinal co-culture model responded to Salmonella infection by upregulating genes involved in inflammation, tissue remodeling, and wound healing at higher levels when the bacteria were grown under simulated microgravity conditions prior to use in infection studies. This was observed for both wild type and hfq mutant strains of the pathogen.

Data from this new spaceflight analog study reinforces previous findings from the team's 2006, 2008 and 2010 Space Shuttle experiments. In particular, the 2010 flight experiment conducted aboard Space Shuttle Discovery, called STL-IMMUNE, used the same wild type strain of S. Typhimurium to infect a 3-D model of human intestinal tissue made from the same epithelial cells used in the new study.

Several commonalities were observed between host cell responses to infection in the new spaceflight analog study and those previously reported when infections took place in true spaceflight during the STL-IMMUNE experiment. These results further reinforce the RWV as a predictive ground-based spaceflight analogue culture system that mimics key aspects of microbial responses to true spaceflight culture.

"During STL-IMMUNE, we discovered that infection of a human 3-D intestinal epithelial model by Salmonella during spaceflight induced key transcriptional and proteomic biosignatures that were consistent with enhanced infection by the pathogen," Barrila says. "However, due to the technical challenges of performing in-flight infections, we could not quantify whether the bacteria were actually attaching and invading into the tissue at higher levels. The use of the RWV bioreactor as a spaceflight analog culture system in our current study has been a powerful tool which allowed us to explore this experimental question at a deeper level."

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Novel nanoantibiotics kill bacteria without harming healthy cells

The Centers for Disease Control and Prevention estimates that more than 2.8 million Americans experience antibiotic-resistant infections each year; more than 35,000 die from those infections.

To address this critical and worldwide public health issue, a team of researchers led by Hongjun (Henry) Liang, Ph.D., from the Texas Tech University Health Sciences Center (TTUHSC) Department of Cell Physiology and Molecular Biophysics, recently investigated whether or not a series of novel nanoparticles can kill some of the pathogens that lead to human infection without affecting healthy cells.

The study, "Hydrophilic Nanoparticles that Kill Bacteria while Sparing Mammalian Cells Reveal the Antibiotic Role of Nanostructures," was published Jan. 11 by Nature Communications. Other study members of the Liang team, all from TTUHSC, included Yunjiang Jiang, Ph.D., Wan Zheng, Ph.D., Keith Tran, Elizabeth Kamilar, Jitender Bariwal, Ph.D., and Hairong Ma, Ph.D.

Past research has shown that hydrophobicity (a molecule's ability to repel water) and hydrophilicity (a molecule's ability to attract and dissolve in water) affects cells; the more hydrophobic a substance is, the more adverse the reaction it will cause. However, Liang said, there is no quantitative standard for how much hydrophobicity is acceptable.

"Basically, you can kill bacteria when you increase hydrophobicity," Liang said. "But it will also kill healthy cells, and we don't want that."

For their study, the Liang team used novel hydrophilic nanoparticles known as nanoantibiotics that were developed by Liang's laboratory. Structurally speaking, these novel nanoantibiotics resemble tiny hairy spheres, each composed of many hydrophilic polymer brushes grafted onto silica nanoparticles of different sizes.

These synthetic compounds, which Liang's lab produces, are designed to kill bacteria via membrane disruptions like antimicrobial peptides do, but through a different mode of membrane remodeling that damages bacterial membranes and not mammalian cells. Antimicrobial peptides are a diverse class of amphipathic molecules (partially hydrophilic-partially hydrophobic), which occur naturally and serve as the first line of defense for all multicellular organisms. The direct use of antimicrobial peptides as antibiotics is limited by their stability and toxicity.

There have been other studies in which researchers grafted amphipathic molecules onto nanoparticles, and they too kill bacteria. However, Liang said the primary issue in using amphipathic molecules is that it becomes very difficult to strike the right balance between their hydrophobicity and hydrophilicity so that the toxicity of these molecules to our own cells is significantly reduced.

"In our case, we remove that uncertainty from the equation because we started with a hydrophilic polymer," Liang pointed out. "The cytotoxicity of hydrophobic moieties is not a concern anymore. Those hydrophilic polymers by themselves, or the silica nanoparticles alone don't kill bacteria; they have to be grafted onto the nanostructure to be able to kill bacteria. And so, this is the first important discovery."

The Liang team also discovered that the degree of antibiotic activity is affected by the size of the hairy spheres, which according to Liang is the second important discovery of this research. Those measuring 50 nanometers and below appear to be much more active than those whose size exceeds 50 nanometers. Liang said those measuring approximately 10 nanometers appear to be the most active. (Using synchrotron small angle x-ray scattering and other methods, the Liang team is able to interpret the molecular mechanism of the size-dependent antibiotic activity.)

These discoveries are important because using nanoantibiotics to kill bacteria evades all known mechanisms of bacterial resistance unless bacteria completely revamp their pathways for making cell membranes, which Liang said is unlikely.

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Cat bacteria treats mouse skin infection, may help you and your pets as well

Researchers at University of California San Diego School of Medicine used bacteria found on healthy cats to successfully treat a skin infection on mice. These bacteria may serve as the basis for new therapeutics against severe skin infections in humans, dogs and cats.

The study, published in eLife on October 19, 2021, was led by Richard L. Gallo, MD, PhD, Distinguished Professor and chair of the Department of Dermatology at UC San Diego School of Medicine, whose team specializes in using bacteria and their products to treat illnesses -- an approach known as "bacteriotherapy."

Skin is colonized by hundreds of bacterial species that play important roles in skin health, immunity and fighting infection. All species need to maintain a diverse balance of healthy skin bacteria to fight potential pathogens.

"Our health absolutely depends on these 'good' bacteria," said Gallo. "They rely on our healthy skin to live, and in return some of them protect us from 'bad' bacteria. But if we get sick, 'bad' bacteria can take advantage of our weakened defenses and cause infection."

This is the case with methicillin-resistant Staphylococcus pseudintermedius (MRSP), a bacterium commonly found on domesticated animals that becomes infectious when the animals are sick or injured. MRSP is an emerging pathogen that can jump between species and cause severe atopic dermatitis, or eczema. These infections are common in dogs and cats, and can also occur in humans, though rates of human infection vary around the world. As its name suggests, MRSP is resistant to common antibiotics and has been difficult to treat in clinical and veterinary settings.

To address this, researchers first screened a library of bacteria that normally live on dogs and cats and grew them in the presence of MRSP. From this, they identified a strain of cat bacteria called Staphylococcus felis (S. felis) that was especially good at inhibiting MRSP growth. They found that this special strain of S. felis naturally produces multiple antibiotics that kill MRSP by disrupting its cell wall and increasing the production of toxic free radicals.

"The potency of this species is extreme," said Gallo. "It is strongly capable of killing pathogens, in part because it attacks them from many sides -- a strategy known as 'polypharmacy.' This makes it particularly attractive as a therapeutic."

Bacteria can easily develop resistance to a single antibiotic. To get around this, S. felis has four genes that code for four distinct antimicrobial peptides. Each of these antibiotics is capable of killing MRSP on their own, but by working together, they make it more difficult for the bacteria to fight back.

Having established how S. felis kills the MRSP, the next step was to see whether it could work as a therapy on a live animal. The team exposed mice to the most common form of the pathogen and then added either S. felis bacteria or bacterial extract to the same site. The skin showed a reduction in scaling and redness after either treatment, compared with animals that had no treatment. There were also fewer viable MRSP bacteria left on the skin after treatment with S. felis.

Next steps include plans for a clinical trial to confirm whether S. felis can be used to treat MRSP infections in dogs. Bacteriotherapies like this one can be delivered via topical sprays, creams or gels that contain either live bacteria or purified extract of the antimicrobial peptides.

While these products are in development, what should pet owners do in the meantime?

"Don't stop washing your pets to keep these 'good' bacteria on them," said Gallo. "Skin has evolved to protect the 'good' bacteria, so soap and detergents don't usually wash the good guys off."

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COVID-19 nasal vaccine candidate effective at preventing disease transmission, study shows

Breathe in, breathe out. That's how easy it is for SARS-CoV-2, the virus that causes COVID-19, to enter your nose. And though remarkable progress has been made in developing intramuscular vaccines against SARS-CoV- 2, such as the readily available Pfizer, Moderna and Johnson & Johnson vaccines, nothing yet -- like a nasal vaccine -- has been approved to provide mucosal immunity in the nose, the first barrier against the virus before it travels down to the lungs.

But now, we're one step closer.

Navin Varadarajan, University of Houston M.D. Anderson Professor of Chemical and Biomolecular Engineering, and his colleagues, are reporting in iScience the development of an intranasal subunit vaccine that provides durable local immunity against inhaled pathogens.

"Mucosal vaccination can stimulate both systemic and mucosal immunity and has the advantage of being a non-invasive procedure suitable for immunization of large populations," said Varadarajan. "However, mucosal vaccination has been hampered by the lack of efficient delivery of the antigen and the need for appropriate adjuvants that can stimulate a robust immune response without toxicity."

To solve those problems, Varadarajan collaborated with Xinli Liu, associate professor of pharmaceutics at the UH College of Pharmacy, and an expert in nanoparticle delivery. Liu's team was able to encapsulate the agonist of the stimulator of interferon genes (STING) within liposomal particles to yield the adjuvant named NanoSTING. The function of the adjuvant is to promote the body's immune response.

"NanoSTING has a small particle size around 100 nanometers which exhibits significantly different physical and chemical properties to the conventional adjuvant," said Liu.

"We used NanoSTING as the adjuvant for intranasal vaccination and single-cell RNA-sequencing to confirm the nasal-associated lymphoid tissue as an inductive site upon vaccination. Our results show that the candidate vaccine formulation is safe, produces rapid immune responses -- within seven days -- and elicits comprehensive immunity against SARS-CoV-2," said Varadarajan.

A fundamental limitation of intramuscular vaccines is that they are not designed to elicit mucosal immunity. As prior work with other respiratory pathogens like influenza has shown, sterilizing immunity to virus re-infection requires adaptive immune responses in the respiratory tract and the lung.

The nasal vaccine will also serve to equitably distribute vaccines worldwide, according to the researchers. It is estimated that first world countries have already secured and vaccinated multiple intramuscular doses for each citizen while billions of people in countries like India, South Africa, and Brazil with large outbreaks are currently unimmunized. These outbreaks and viral spread are known to facilitate viral evolution leading to decreased efficacy of all vaccines.

"Equitable distribution requires vaccines that are stable and that can be shipped easily. As we have shown, each of our components, the protein (lyophilized) and the adjuvant (NanoSTING) are stable for over 11 months and can be stored and shipped without the need for freezing," said Varadarajan.

Varadarajan is co-founder of AuraVax Therapeutics Inc., a pioneering biotech company developing novel intranasal vaccines and therapies to help patients defeat debilitating diseases, including COVID-19. The company has an exclusive license agreement with UH with respect to the intellectual property covering intranasal vaccines and STING agonist technologies. They have initiated the manufacturing process and plan to engage the FDA later this year.

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Secret garden: Drug-resistant pathogen strains meet and evolve on plant bulbs

Just when we thought it was safe to go to the local garden center, researchers from Japan have discovered that fungicide-resistant strains of a nasty pathogen have been getting up to no good among the tulip bulbs.

In a study published in August in Environmental Microbiology researchers from the University of Tsukuba and Chiba University have revealed that plant bulbs harboring a potentially lethal pathogen also make the perfect lab for evolving fungicide-resistant strains.

The risk associated with fungal infections is increasing, with occurrences of pulmonary aspergillosis (PA), a deadly fungal infection caused by the human pathogen Aspergillus fumigatus, rising globally. Of particular concern are influenza-related PA and COVID-19-related PA, the case numbers of which are growing quickly. Azoles -- a class of antifungal compounds often used as antifungal drugs to treat aspergillosis -- are also widely used as agricultural fungicides. Azole-resistant strains of A. fumigatus are spreading in the environment, potentially promoted by agricultural azole use. Azole resistance is a factor known to affect the treatment of PA, and there is concern that this problem is only worsening.

"Understanding how the genetic variation linked with azole resistance in A. fumigatus strains is distributed and enriched in the environment is necessary for suppressing resistant strains," says senior author of the study Daisuke Hagiwara. "In this study, we set out to do this by investigating the genetics of those strains."

Previously, the research team found several azole-resistant A. fumigatus strains attached to imported plant bulbs for sale in Japanese gardening shops. In this study, they investigated eight strains of azole-resistant A. fumigatus isolated from a single tulip bulb bought in Japan. The researchers used genome sequencing and comparative analysis, and compared the strains for sensitivity to agricultural and medical azoles, in addition to other classes of fungicides. The results indicated that there had previously been genetic recombination between the strains, and that some of them exhibited tolerance to other fungicide classes.

"Our results show that plant bulbs provide not just a vehicle for this pathogen, but also an ideal niche for its strains to encounter each other, and to evolve their resistance to drugs," says Hagiwara.

This study fills gaps in the knowledge of azole-resistant A. fumigatus, providing important information on the genetics behind an urgent global One Health challenge. The research team's findings will inform a deeper understanding of drug-resistant fungi and help with the development of future solutions to this problem.

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How plankton hold secrets to preventing pandemics

Whether it's plankton exposed to parasites or people exposed to pathogens, a host's initial immune response plays an integral role in determining whether infection occurs and to what degree it spreads within a population, new University of Colorado Boulder research suggests.

The findings, published May 13 in The American Naturalist, provide valuable insight for understanding and preventing the transmission of disease within and between animal species. From parasitic flatworms transmitted by snails into humans in developing nations, to zoonotic spillover events from mammals and insects to humans -- which have caused global pandemics like COVID-19 and West Nile virus -- an infected creature's immune response is a vital variable to consider in calculating what happens next.

"One of the biggest patterns that we're seeing in disease ecology and epidemiology is the fact that not all hosts are equal," said Tara Stewart Merrill, lead author of the paper and a postdoctoral fellow in ecology. "In infectious disease research, we want to build host immunity into our understanding of how disease spreads."

Invertebrates are common vectors for disease, which means they can transmit infectious pathogens between humans or from animals to humans. Vector-borne diseases, like malaria, account for almost 20% of all infectious diseases worldwide and are responsible for more than 700,000 deaths each year.

Yet epidemiological studies have rarely considered invertebrate immunity and recovery in creatures that are vectors for human disease. They assume that once exposed to a pathogen, the invertebrate host will become infected.

But what if it was possible for invertebrates to fight off these diseases, and break the link in the chain that passes them on to humans?

While observing a tiny species of zooplankton (Daphnia dentifera) throughout its lifecycle and exposure to a fungal parasite (Metschnikowia bicuspidata), the researchers saw this potential in action. Some of the plankton were good at stopping fungal spores from entering their bodies, and others cleared the infection within a limited window of time after ingesting the spores.

"Our results show that there are several defenses that invertebrates can use to reduce the likelihood of infection, and that we really need to understand those immune defenses to understand infection patterns," said Stewart Merrill.

Unexpected recovery

Stewart Merrill started this work in her first year as a doctoral student at the University of Illinois, studying this little plankton and its collection of defenses. It's a gruesome process if the plankton fails to ward off the parasite: Its fungal spores attack the plankton's gut, fill its body and grow until they are released when the host finally dies.

But she noticed something that had not been recorded before: Some of the doomed plankton recovered. Several years later, she has found that when faced with identical levels of exposure, the success or failure of these infections depends on the strength of the host's internal defenses during this early limited window of opportunity.

Based on their observations of these individual outcomes, the researchers developed a simple probabilistic model for measuring host immunity that can be applied across wildlife systems, with important applications for diseases transmitted to humans by invertebrates.

"When immune responses are good, they act as a filter that reduces transmission," said Stewart Merrill. "But any environmental change that degrades immunity can actually amplify transmission, because it will let all of that exposure go through and ultimately become infectious."

It's a model that can also apply to COVID-19, as research from CU Boulder has shown that not all hosts are the same in transmitting the coronavirus, and exposure does not directly determine infection.

COVID-19 is also believed to be the result of a zoonotic spillover, an infection that moved from animals into people, and similar probabilistic models could be advantageous in predicting the occurrence and spread of future spillover events, said Stewart Merrill.

Understanding prevention of infection

Stewart Merrill hopes that a better understanding of infections in a simple animal like plankton can be applied more broadly to invertebrates that matter for human health.

In Africa, Southeast Asia, as well as South and Central America, 200 million people suffer from infections caused by schistosomes -- invertebrates more commonly known as parasitic flatworms. They cause illness and death, and significant economic and public health consequences, so much so that the World Health Organization considers them the second-most socioeconomically devastating parasitic disease after malaria.

They're just one of many neglected tropical diseases transmitted to people by invertebrate hosts such as snails, mosquitoes and biting flies. These diseases infect a large portion of a population but occur in areas with low levels of sanitation that don't have the economic resources to address those diseases, said Stewart Merrill.

Schistosomes live in freshwater environments that people use for their drinking water, laundry and bathing. So even though there are treatments, the next day a person can easily get reinfected just by accessing the water they need. By better understanding how the flatworms themselves succumb to or fight off infection, scientists like Stewart Merrill help us get closer to stopping the chain of transmission into humans.

"We really need to work on understanding prevention of infection, and what that risk is in those aquatic systems, rather than just cures for infection," she said.

The good news is we can learn from the same invertebrates which infect us. In invertebrate hosts that suffer or die from their infections, there is a good incentive to learn how to build an immune response and fight it off. Some snails have even shown the ability to retain an immunological memory: If they get infected once and survive, then they might never get infected again.

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How the immune system remembers viruses

 When a virus enters the body, it is picked up by certain cells of the immune system. They transport the virus to the lymph nodes where they present its fragments, known as antigens, to CD8+ T cells responsible control of viral infections. Each of these cells carries a unique T cell receptor on the surface that can recognize certain antigens. However, only very few T cell receptors match a given viral the antigen.

To bring the infection under control and maximize the defenses against the virus, these few antigen-specific T cells start dividing rapidly and develop into effector T cells. These kill virus-infected host cells and then die off themselves once the infection is cleared. Some of these short-lived effector cells -- according to the generally accepted theory -- turn into memory T cells, which persist in the organism long term. In case the same pathogen enters the body again, memory T cells are already present and ready to fight the invader more swiftly and effectively than during the first encounter.

Memory cells and their origin

"Prevailing scientific opinion says that activated T cells first become effector cells and only then gradually develop into memory cells," says Dr. Veit Buchholz, a specialist in microbiology and working group leader at the Institute for Medical Microbiology, Immunology and Hygiene at TUM. "In our view, however, that isn't the case. It would mean that the more effector cells are formed after contact with the pathogen, the more numerous the memory cells would become." However, Buchholz and his colleagues observed a different course of events and have now published their results in the journal Nature Immunology.

"We investigated the antiviral immune responses resulting from individual activated T cells in mice and traced the lineage of the ensuing memory cells using single-cell fate mapping," reports first author Dr. Simon Grassmann. "Based on these experiments, we were able to show that certain 'T cell families' descended from individual cells form up to 1000 times more 'memory' than others. However, these long-term dominating T cell families only contributed little to the magnitude of the initial immune response, which was dominated by effector cells derived from other shorter-lived T cell families."

At the level of individual cells, it therefore became evident that development of effector and memory cells segregates at a much earlier stage than previously believed: "Already in the first week after the confrontation with the pathogen, we saw major differences in the transcriptomes of the detected T cell families," says Lorenz Mihatsch, also a first author of the study. "Normally at this time of the immune response CD8+ T cells are enriched in molecules that help to kill virus infected cells. However, we found no indication of these cytolytic molecules in the long-term dominating T cell families. Instead, they were already geared exclusively towards memory development at this early stage."

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Sea otters, opossums and the surprising ways pathogens move from land to sea

Sea otter eating clam

A parasite known only to be hosted in North America by the Virginia opossum is infecting sea otters along the West Coast. A study from the University of California, Davis, elucidates the sometimes surprising and complex pathways infectious pathogens can move from land to sea to sea otter.

For the study, published in the journal Scientific Reports, researchers tested sea otters ranging from Southern California to Alaska for the presence of Sarcocystis neurona, a parasite and important cause of death in sea otters.

They were surprised to find several infected sea otters in the northern part of Vancouver Island in British Columbia, where Virginia opossums -- also known as the North American opossum -- are not known to live. They wondered: Could this parasite travel very long distances in water, or is there an additional unknown host for this pathogen?

To answer this question, the scientists examined spatial patterns and previous research into pathogen transmission, diet and movement of otters. Their results suggest the pathogen may be carried by water runoff from land to sea, where it can be concentrated through ocean movement and prey species, such as clams.

Learning from Otters and Cats

A related parasite, Toxoplasma gondii, is also known to kill sea otters. Decades of research by a consortium of scientists led by UC Davis School of Veterinary Medicine and the California Department of Fish and Wildlife traced that parasite to another land-based mammal -- wild and domestic cats near watersheds.

"We know S. neurona kills sea otters, and we were pretty sure it comes from the land, but we didn't really know how this pathogen finds them," said lead author Tristan Burgess, a doctoral student in the lab of Christine Kreuder Johnson at the UC Davis One Health Institute at the time of the study. "This new research suggests that there may be a long and complex transmission pathway, a little like the way Toxoplasma finds sea otters, but with a different cast of characters."

Risk Factors

Most infections occurred in California and Washington, more so than Alaska and British Columbia. The study found that higher risks of exposure were associated with:

• Adult male otters.
• Human-dense habitats, some wetlands and croplands.
• Wetlands can help filter and deactivate some pathogens, but the study noted they may be potential opossum habitat, as well.
• Habitats of soft sediment, like the mouths of rivers and estuaries.
• Otters consuming a diet rich in clams, where the parasite may be concentrated.

Marine Mammal Sentinels

This study highlights risk factors for one species' exposure to one parasite. But it also provides a better understanding of how parasites and infection can move from land to sea to marine mammals.

"Seemingly unimportant species can be important in unexpected ways," Burgess said. "We should also remember the value of marine mammals as sentinels, not just of the health of their marine habitat, but of nearby terrestrial environments, too."

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Your energy-efficient washing machine could be harboring pathogens

For the first time ever, investigators have identified a washing machine as a reservoir of multidrug-resistant pathogens. The pathogens, a single clone of Klebsiella oxytoca, were transmitted repeatedly to newborns in a neonatal intensive care unit at a German children's hospital. The transmission was stopped only when the washing machine was removed from the hospital. The research is published this week in Applied and Environmental Microbiology, a journal of the American Society for Microbiology.

"This is a highly unusual case for a hospital, in that it involved a household type washing machine," said first author Ricarda M. Schmithausen, PhD. Hospitals normally use special washing machines and laundry processes that wash at high temperatures and with disinfectants, according to the German hospital hygiene guidelines, or they use designated external laundries.

The research has implications for household use of washers, said Dr. Schmithausen, Senior Physician, Institute for Hygiene and Public Health, WHO Collaboration Center, University Hospital, University of Bonn, Germany. Water temperatures used in home washers have been declining, to save energy, to well below 60°C (140°F), rendering them less lethal to pathogens. Resistance genes, as well as different microorganisms, can persist in domestic washing machines at those reduced temperatures, according to the report.

"If elderly people requiring nursing care with open wounds or bladder catheters, or younger people with suppurating injuries or infections live in the household, laundry should be washed at higher temperatures, or with efficient disinfectants, to avoid transmission of dangerous pathogens," said Martin Exner, MD, Chairman and Director of the Institute for Hygiene and Public Health, WHO Collaboration Center, University Hospital/University of Bonn. "This is a growing challenge for hygienists, as the number of people receiving nursing care from family members is constantly increasing."

At the hospital where the washing machine transmitted K. oxytoca, standard screening procedures revealed the presence of the pathogens on infants in the ICU. The researchers ultimately traced the source of the pathogens to the washing machine, after they had failed to find contamination in the incubators or to find carriers among healthcare workers who came into contact with the infants.

The newborns were in the ICU due mostly to premature birth or unrelated infection.The clothes that transmitted K. oxytoca from the washer to the infants were knitted caps and socks to help keep them warm in incubators, as newborns can quickly become cold, even in incubators, said Dr. Exner.

The investigators assume that the pathogens "were disseminated to the clothing after the washing process, via residual water on the rubber mantle [of the washer] and/or via the final rinsing process, which ran unheated and detergent-free water through the detergent compartment," implicating the design of the washers, as well as the low heat, according to the report. The study implies that changes in washing machine design and processing are required to prevent the accumulation of residual water where microbial growth can occur and contaminate clothes.

However, it still remains unclear how, and via what source the pathogens got into the washing machine.

The infants in the intensive care units (ICU) were colonized, but not infected by K. oxytoca. Colonization means that pathogens are harmlessly present, either because they have not yet invaded tissues where they can cause disease, or because the immune system is effectively repelling them.

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