This research is published in PLoS Biology in the paper, “Multi-drug resistant E. coli encoding high genetic diversity in carbohydrate metabolism genes displace commensal E. coli from the intestinal tract.”

“Antibiotic resistance has been hailed as one of the biggest health problems of our time by the World Health Organization, noted Alan McNally, PhD, professor at the Institute of Microbiology and Infection at the University of Birmingham, U.K. “There are further problems looming unless we get a better understanding of what is happening so that further drug resistance can be halted in its tracks.”

“Scientists have long questioned what makes certain types of E. coli successful multi-drug resistant pathogens,” McNally continues. “It seems that extra-intestinal pathogenic E. coli, which cause urinary tract and bloodstream infections, are particularly successful when it comes to developing resistance and are therefore especially tricky to treat. Our study provides evidence that certain types of E. coli are more prone to develop antibiotic resistance than others.”

The researchers first showed that both multi-drug resistant and non-resistant gut-dwelling E. coli were found to easily colonize a mammalian gut. In addition, using mice colonized with non-MDR E. coli strains, a challenge with MDR E. coli (either by oral gavage or co-housing with colonized mice) resulted in displacement and dominant intestinal colonization by MDR E. coli ST131.

The researchers went on to determine, using a functional pangenomic analysis of 19,571 E. coli genomes, that “carriage of AMR genes is associated with increased diversity in carbohydrate metabolism genes.”

Although some strains of E. coli are harmless, others can cause illness, including diarrhea, urinary tract infections, and often-fatal bloodstream infections. More severe infections are usually treated with antibiotics but the rise in multidrug resistance strains of E. coli is concerning. Previous work shows that multi-drug resistance alone is not sufficient to drive strains to complete dominance.

This study suggests that “independent of antibiotic selective pressures, MDR E. coli display a competitive advantage to colonize the mammalian gut and points to a vital role of metabolism in the evolution and success of MDR lineages of E. coli via carriage and spread.”

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Now researchers have uncovered how the fungus Candida albicans enters the brain, activates two separate mechanisms in brain cells that promote its clearance, and generates amyloid beta (Ab)-like peptides—toxic protein fragments from the amyloid precursor protein that are considered to be at the center of the development of Alzheimer’s disease. More specifically, they show that C. albicans “activates microglia through two mechanisms involving the production of amyloid b-like peptides that signal through TLR4 and candidalysin that activates CD11b, together promoting clearance of C. albicans from the brain.”

This work is published in Cell Reports in the paper, “Toll-like receptor 4 and CD11b. expressed on microglia coordinate eradication of Candida albicans cerebral mycosis.”

“Our lab has years of experience studying fungi, so we embarked on the study of the connection between C. albicans and Alzheimer’s disease in animal models,” said David Corry, MD, professor of pathology and immunology and medicine at Baylor College School of Medicine. “In 2019, we reported that C. albicans does get into the brain where it produces changes that are very similar to what is seen in Alzheimer’s disease. The current study extends that work to understand the molecular mechanisms.”

First, they show that C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted aspartic proteinases (Saps) and candidalysin.

“Our first question was, how does C. albicans enter the brain? We found that C. albicans produces enzymes (called secreted aspartic proteases or Saps) that breakdown the blood-brain barrier, giving the fungus access to the brain where it causes damage,” said Yifan Wu, MD, PhD, postdoctoral scientist in pediatrics working in the Corry lab.

Corry and his colleagues had previously shown that a C. albicans brain infection is fully resolved in otherwise healthy mice after 10 days. In this study, they reported that this occurred thanks to two mechanisms triggered by the fungus in microglia.

“The same Saps that the fungus uses to break the blood-brain barrier also break down the amyloid precursor protein into Ab-like peptides,” Wu said. “These peptides activate microglial brain cells via a cell surface receptor called Toll-like receptor 4 (TLR4), which keeps the fungi load low in the brain, but does not clear the infection.”

C. albicans also produces the candidalysin protein that binds to microglia via the CD11b receptor. “Candidalysin-mediated activation of microglia is essential for clearance of Candida in the brain,” Wu said. “If we take away this pathway, fungi are no longer effectively cleared in the brain.”

The authors summarized, “The Saps hydrolyze amyloid precursor protein (APP) into amyloid b (Ab)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while candidalysin engages the integrin CD11b (Mac-1) on microglia.”

“This work potentially contributes an important new piece of the puzzle regarding the development of Alzheimer’s disease,” Corry said. “The current explanation for this condition is that it is mostly the result of the accumulation of toxic Ab-like peptides in the brain that leads to neurodegeneration. The dominant thinking is that these peptides are produced endogenously, our own brain proteases break down the amyloid precursor proteins generating the toxic Ab peptides.”

Here, the researchers showed that the Ab-like peptides also can be generated from a different source—C. albicans. This common fungus, which has been detected in the brains of people with Alzheimer’s disease and other chronic neurodegenerative disorders, has its own set of proteases that can generate the same Ab-like peptides the brain can generate endogenously.

“We propose that the brain Ab-peptide aggregates that characterize multiple Candida-associated neurodegenerative conditions including Alzheimer’s disease, Parkinson’s disease, and others, may be generated both intrinsically by the brain and by C. albicans,” Corry said. “These findings in animal models support conducting further studies to evaluate the role of C. albicans in the development of Alzheimer’s disease in people, which can potentially lead to innovative therapeutic strategies.”

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“The functional role of CD8⁺ lymphocytes in tuberculosis remains poorly understood. We depleted innate and/or adaptive CD8⁺ lymphocytes in macaques and showed that loss of all CD8α⁺ cells (using anti-CD8α antibody) significantly impaired early control of Mycobacterium tuberculosis (Mtb) infection, leading to increased granulomas, lung inflammation, and bacterial burden,” wrote the investigators.

“Analysis of barcoded Mtb from infected macaques demonstrated that depletion of all CD8⁺ lymphocytes allowed increased establishment of Mtb in lungs and dissemination within lungs and to lymph nodes, while depletion of only adaptive CD8⁺ T cells (with anti-CD8β antibody) worsened bacterial control in lymph nodes.

“Flow cytometry and single-cell RNA sequencing revealed polyfunctional cytotoxic CD8⁺ lymphocytes in control granulomas, while CD8-depleted animals were unexpectedly enriched in CD4 and γδ T cells adopting incomplete cytotoxic signatures. Ligand-receptor analyzes identified IL-15 signaling in granulomas as a driver of cytotoxic T cells. These data support that CD⁸⁺ lymphocytes are required for early protection against Mtb and suggest polyfunctional cytotoxic responses as a vaccine target.

“This is an unusual finding,” said senior author JoAnne Flynn, PhD, distinguished professor and chair of microbiology and molecular genetics at Pitt. “No one before us has shown that CD8+ lymphocytes make a difference early in the infection in a translatable nonhuman primate model, but our findings suggest that these innate immune cell populations are actually playing an important role in restraining the initial infection.”

Two phases

The immune response over the course of tuberculosis infection has two phases. The first six weeks after the infection are characterized by the influx of quick-acting immune cells that rush to the site of infection, be that the airways or the lung, to kill the bug and limit the damage quickly, by all means necessary.

Unlike the early innate immune response, the adaptive immune response that emerges after eight to 10 weeks of infection is more fine-tuned and aimed at precisely targeting the specific infection-causing pathogen and killing it as efficiently as possible.

In general, the exact dynamics of the immune response in tuberculosis, and the role of fast-acting CD8+ lymphocytes was unclear.

Flynn and her team found that the infection was developing a lot faster and spreading further in macaque monkeys whose innate CD8+ cells were depleted than in monkeys whose total CD8+ T cell population was intact, or whose adaptive CD8+ T cells were removed, suggesting that innate CD8+ cells play a crucial role in limiting the infection in its early stages.

The scientists found that in monkeys with depleted innate CD8+ cells, other immune cells tried to take over the function of fast responders, probably in response to IL-15. But because those cells lack the natural machinery that would enable them to deliver molecules that could kill the bacterium, the infection-clearing immune response was incomplete.

As a next step in their research, scientists are studying whether IL-15 administered together with an existing TB vaccine can increase protection and make the vaccine more effective.

The study was a collaboration between Flynn’s lab and Philana Ling Lin, MD, of the UMPC Children’s Hospital of Pittsburgh, Alex Shalek, PhD, of MIT, and Sarah Fortune, MD, of Harvard University.

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This work is published in Nature in the paper, “Learning from prepandemic data to forecast viral escape.”

The researchers first developed EVE (evolutionary model of variant effect) in the context of uncovering mutations that cause human diseases. The core of EVE is a generative model that learns to predict the functionality of proteins based on large-scale evolutionary data across species. In a previous study, EVE allowed researchers to discern disease-causing from benign mutations in genes implicated in various conditions, including cancers and heart rhythm disorders.

“You can use these generative models to learn amazing things from evolutionary information—the data have hidden secrets that you can reveal,” said Debora Marks, PhD, associate professor of systems biology in the Blavatnik Institute at Harvard Medical School.

During the pandemic, Marks and her team saw an opportunity to apply EVE. They took the generative model from EVE—which can predict mutations in viral proteins that won’t interfere with the virus’s function—and added biological and structural details about the virus, including information about regions most easily targeted by the immune system.

“We’re taking biological information about how the immune system works and layering it on our learnings from the broader evolutionary history of the virus,” explained co-lead author Nicole Thadani, a former research fellow in the Marks lab.

Such an approach, Marks emphasized, means that EVEscape has a flexible framework that can be easily adapted to any virus.

In the new study, the team turned the clock back to January 2020, just before the COVID-19 pandemic started. Then they asked EVEscape to predict what would happen with SARS-CoV-2.

“It’s as if you have a time machine. You go back to day one, and you say, I only have that data, what am I going to say is happening?” Marks said.

EVEscape predicted which SARS-CoV-2 mutations would occur during the pandemic with accuracy similar to this of experimental approaches that test the virus’s ability to bind to antibodies made by the immune system. EVEscape outperformed experimental approaches in predicting which of those mutations would be most prevalent. More importantly, EVEscape could make its predictions more quickly and efficiently than lab-based testing since it didn’t need to wait for relevant antibodies to arise in the population and become available for testing.

The researchers are now using EVEscape to look ahead at SARS-CoV-2 and predict future variants of concern; every two weeks, they release a ranking of new variants. Eventually, this information could help scientists develop more effective vaccines and therapies. The team is also broadening the work to include more viruses as they demonstrated that EVEscape could be generalized to other viruses, including HIV and influenza.

“We want to know if we can anticipate the variation in viruses and forecast new variants— because if we can, that’s going to be extremely important for designing vaccines and therapies,” notes Marks.

Additionally, EVEscape predicted which antibody-based therapies would lose their efficacy as the pandemic progressed and the virus developed mutations to escape these treatments. The tool was also able to sift through the tens of thousands of new SARS-CoV-2 variants produced each week and identify the ones most likely to become problematic.

“By rapidly determining the threat level of new variants, we can help inform earlier public health decisions,” said Sarah Gurev, a graduate student in the Marks lab from the Electrical Engineering and Computer Science program at MIT.

The team is now applying EVEscape to SARS-CoV-2 in real time, using all of the information available to make predictions about how it might evolve next. They are also testing EVEscape on understudied viruses such as Lassa and Nipah, two pathogens of pandemic potential for which relatively little information exists. Such less-studied viruses can have a huge impact on human health across the globe, the researchers noted.

The researchers publish a biweekly ranking of new SARS-CoV-2 variants on their website and share this information with entities such as the World Health Organization. The complete code for EVEscape is also freely available online.

Another important application of EVEscape would be to evaluate vaccines and therapies against current and future viral variants. The ability to do so can help scientists design treatments that are able to withstand the escape mechanisms a virus acquires.

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Now, for the first time, genome editing has generated chickens partially resistant to infection by influenza virus A. The findings, which indicate that multiple genetic modifications would be required to curtail viral escape, present a potential strategy to help mitigate the spread of avian influenza into farmed poultry from wild bird sources.

This work was published in Nature Communications in the paper, “Creating resistance to avian influenza infection through genome editing of the ANP32 gene family.”

Avian influenza is widely dispersed across Asia, Europe, Africa, and the Americas representing a threat to wild bird species, economic costs to farmers, and risk to human health. Poultry vaccination against avian influenza has not yet been reliable due to the rapid antigenic drift of field viruses and is controversial owing to political and economic implications. In chickens, avian influenza relies on the host protein ANP32A for its life cycle, which represents a potential target for creating virus-resistant birds.

Researchers edited the ANP32A gene in chicken germ cells to restrict influenza A activity. More specifically, the authors used CRISPR/Cas9 to generate homozygous gene-edited chickens containing two ANP32A amino acid substitutions that prevent viral polymerase interaction. They found that fully-grown chickens were resistant to a physiological dose of influenza A exposure from other infected birds and displayed increased resilience. After a challenge with influenza A virus, nine of the ten edited chickens remained uninfected.

However, when the researchers infected with a higher dose (1,000 times higher,) breakthrough infections occurred. The influenza virus, they found, had mutated to be able to use the edited chicken ANP32A. Unexpectedly, the authors wrote, “this virus also replicated in chicken embryos edited to remove the entire ANP32A gene and instead co-opted alternative ANP32 protein family members, chicken ANP32B and ANP32E.”

The birds showed no adverse health or egg-laying productivity effects when monitored for over two years. The authors suggest that additional editing and deletion of the other associated genes (ANP32B and ANP32E) in chicken cells would prevent virus replication.

The findings suggest gene editing as a possible route to create chickens resistant to infection by avian influenza. However, the authors caution that further study is needed to ensure animal health is not impacted and that multiple edits to the ANP32 family of genes might be required to eliminate the possibility of viral evolution.

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Their findings are published in Science in an article titled, “PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection,” and led by Eva Frickel, PhD, senior Wellcome Trust fellow at the University of Birmingham.

The research reveals how GBP1 is controlled through a process called phosphorylation, a process in which a phosphate group is added to a protein by enzymes called protein kinases. The kinase targeting GBP1 is called PIM1 and can also become activated during inflammation. Phosphorylated GBP1 in turn is bound to a scaffold protein, which keeps uninfected bystander cells safe from uncontrolled GBP1 membrane attack and cell death.

The mechanism blocks GPB1 from attacking cell membranes indiscriminately, creating a guard mechanism that is sensitive to disruption by the actions of pathogens inside the cells. The new discovery was made by Daniel Fisch, a former PhD student in the Frickel lab working on the study.

“This discovery is significant for several reasons, said Frickel. “Firstly, guard mechanisms such as the one that controls GBP1 were known to exist in plant biology, but less so in mammals. Think of it as a lock and key system. GPB1 wants to go out and attack cellular membranes, but PIM1 is the key meaning GPB1 is locked safely away.”

“The second reason is that this discovery could have multiple therapeutic applications. Now we know how GBP1 is controlled, we can explore ways to switch this function on and off at will, using it to kill pathogens.”

Frickel and her team conducted this initial research on Toxoplasma gondii, a single-celled parasite that is common in cats. While Toxoplasma infections in Europe and Western countries are unlikely to cause serious illness, in South American countries it can cause reoccurring eye infections and blindness and is particularly dangerous for pregnant women.

The researchers found that Toxoplasma blocks inflammatory signaling within cells, preventing PIM1 from being produced, meaning that the “lock and key” system disappears, liberating GBP1 to attack the parasite. Switching PIM1 “off’ with an inhibitor or by manipulating the cell’s genome also resulted in GPB1 attacking Toxoplasma and removing the infected cells.

Frickel continued: “This mechanism could also work on other pathogens, such as Chlamydia, Mycobacterium tuberculosis, and Staphylococcus all major disease-causing pathogens which are increasingly becoming more resistant to antibiotics. By controlling the guard mechanism, we could use the attack protein to eliminate the pathogens in the body. We have already begun looking at this opportunity to see if we are able to replicate what we saw in our Toxoplasma experiments. We are also incredibly excited about how this could be used to kill cancer cells.”

PIM1 is a key molecule in the survival of cancer cells, while GPB1 is activated by the inflammatory effect of cancer. The researchers think that by blocking the interaction between PIM1 and GPB1 they could specifically eliminate cancer cells.

Frickel said: “The implication for cancer treatment is huge. We think this guard mechanism is active in cancer cells, so the next step is to explore this and see if we can block the guard and selectively eliminate cancer cells. There is an inhibitor on the market which we used to disrupt PIM1 and GPB1 interaction. So, if this works, you could use this drug to unlock GPB1 and attack the cancer cells. There is still a very long way to go, but the discovery of the PIM1 guard mechanism could be a massive first step in finding new ways to treat cancer and increasingly antibiotic-resistant pathogens.”

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“It’s an early warning system,” said Brad Spellberg, MD, chief medical officer at the USC-affiliated Los Angeles General Medical Center (formerly LAC+USC). “It’s like Homeland Security putting out a terror alert. ‘Everybody, keep your eyes open. Keep an eye out for suspicious packages’. You’re alerting the soldiers and tanks of your immune system. The vaccine activates them. ‘Oh my, there’s danger here. I better turn into the Hulk.’  I mean, when you have bad superbugs lurking, that’s when you want the Hulk waiting to pounce rather than Dr. Banner, right?”

Spellberg is senior author of the team’s published paper in Science Translational Medicine, which is titled “A protein-free vaccine stimulates innate immunity and protects against nosocomial pathogens.”

Every year, healthcare-associated infections (HAIs) kill more than 90,000 people in the United States and rack up healthcare costs between $28 billion and $45 billion. “On any given day, more than three percent of hospitalized patients in the United States, and four percent in the European Union have an HAI, the authors wrote, citing published figures.

Many such infections are caused by superbugs, including MRSA ( methicillin-resistant Staphylococcus aureus) or Acinetobacter baumannii. “In most cases, HAIs are caused by antimicrobial-resistant (AMR) bacterial and fungal pathogens, which are associated with worse mortality and morbidity than antimicrobial-susceptible pathogens,” the investigators continued. The infections spread via contaminated surfaces or equipment, such as catheters or ventilators, or through person-to-person spread, often from contaminated hands. Risk is highest among intensive care unit patients who may suffer surgical site infections, bloodstream infections, urinary tract infections and ventilator-associated pneumonia.

Moreover, the investigators continued, despite the high incidence of healthcare-acquired infections, there are currently no FDA-approved vaccines that prevent the most serious, antibiotic-resistant infections. “Despite the high incidence of HAIs, there are currently no U.S. Food and Drug Administration–approved vaccines against the most commonly encountered and antibiotic-resistant pathogens …”

Co-author Brian Luna, PhD, assistant professor of molecular microbiology and immunology at Keck School of Medicine of USC, added, “Even if there were such vaccines, multiple vaccines would have to be deployed simultaneously to protect against the full slate of antibiotic-resistant microbes that cause healthcare-acquired infections.”

Typical protein-based vaccines usually prompt the body to make antibodies against a specific pathogen. “Traditional vaccines are “vertical” infection prevention approaches, which activate antigen-specific lymphocytes that target one pathogen at a time,” the team explained. “This single-pathogen targeting makes such vaccines difficult to develop or deploy for the prevention of HAIs, which are caused by myriad bacterial and fungal pathogens … The challenge of implementing such an approach in the hospital setting is that multiple vaccines would have to be deployed simultaneously to protect against the myriad AMR pathogens that cause HAIs.”

The experimental vaccine developed by Spellberg and colleagues is designed to take an entirely different approach, known as trained immunity, that instead mobilizes the body’s preexisting supply of macrophage immune cells that engulf and digest bacteria, fungi and other pathogens. Through this approach these activated fighters, found in all tissues, quickly neutralize incoming invaders which might otherwise multiply rapidly and overwhelm the body’s defenses … “This is very different from developing new antibiotics,” said Jun Yan, a PhD student at Keck School of Medicine of USC and the study’s first author. “This is using our own immune system to fight against different superbugs, which is a different approach than everybody else.”

The protein-free vaccine developed by the team is comprised of just three components, aluminum hydroxide, and monophosphoryl lipid A, which are already used in FDA-approved vaccines, and the antigen fungal mannan, a tiny piece from the surface of a fungus commonly found on human skin. The vaccine is designed to stimulate the innate, rather than the adaptive immune system, the investigators noted.

Tests showed that a single dose of the vaccine worked within 24 hours and lasted for up to 28 days. In mouse infection models, treatment was effective against multiple bacterial and fungal pathogens, boosted the number of pathogen-eating immune cells in the blood, and improved the survival time in animals with invasive blood and lung infections. Early data also suggested that a second dose could extend the window to prevent infection.

“We found that a protein-free, tripartite vaccine improved the survival time in mice infected with varied, high-priority AMR pathogens, including Gram-positive bacteria, Gram-negative bacteria, and fungi, in both models of bacteremia and pneumonia …” the team wrote. And while the degree of efficacy did vary with the different pathogens and other factors such as routes of infection, the investigators also showed that the vaccine was effective—either improving survival time or reducing bacterial burden—in two independent laboratories, testing distinct strains of mice, bacteria, and fungi.

Macrophages were shown to mediate this improved survival in a manner that involved cytokine modulation and epigenetic reprogramming, the team further explained. “The data demonstrate an overall shift to a net anti-inflammatory response to infection, even while upregulating macrophage phagocytosis and enhancing clearance of bacteria in vivo.”

Spellberg, Luna, Yan and Travis Nielsen, formed the startup ExBaq LLC, and the founders have started talks with potential pharmaceutical partners who might be interested in further developing the vaccine for human clinical trials. The USC Stevens Center for Innovation, the technology licensing office for USC, successfully filed one patent for the vaccine and is pursuing others. The National Institute of Allergy and Infectious Diseases has provided ExBaq LLC with a nearly $1 million small business grant.

The next step is getting guidance from the FDA on the requirements to complete preclinical studies and submit and Investigational New Drug Application (IND) in 2024. The first such trial would be done in healthy volunteers to find the right dose of vaccine that is safe and triggers the same kind of immune response in people as seen in the mice.

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A study led by immunobiology experts at Cincinnati Children’s, and described in Cell Reports “Effector memory T cells induce innate inflammation by triggering DNA damage and a non-canonical STING pathway in dendritic cells,” has now unveiled what the researchers suggest are important new details on how two elements of the body’s immune system clash with each other to prompt a chain of reactions that can release deadly floods of cell-killing, organ-damaging cytokines.

“These findings have implications for both autoimmunity as well as cancer,” said co-corresponding author Chandrashekhar Pasare, DVM, PhD, director of the division of immunobiology and co-director of the Center for Inflammation and Tolerance at Cincinnati Children’s. “We have discovered an independent cell signaling pathway that allows a type of immune cell called an effector memory T cell (T_EM) to become a critical driver of innate cytokine storms.”

The chain reaction leading to a cytokine storm appears to start when the effector memory T cells interact with dendritic cells. These starburst shaped cells carry a large collection of receptors to detect various types of invaders. Once they encounter a harmful visitor, dendritic cells latch on and sound an alarm that instructs the rest of the immune system’s machinery to begin producing T cells that are custom designed to eliminate that type of invader.

When the immune system wins the battle, most of the custom T cells stand down. As well as triggering the differentiation of effector T cells that fight the primary infection, the immune system also generates long-lived effector memory T cells that can then respond quickly when they meet DCs carrying signals of reinfection. However, they also have the potential to induce inflammatory responses, the researchers noted.

The scientists have now discovered that ongoing encounters with T_EM cells, such as those occurring when people have autoimmunity or live in a state of chronic inflammation, actually cause DNA strands within dendritic cells to break. This, in turn, prompts a DNA repair pathway that rapidly generates large numbers of inflammatory cytokines, including IL-1b, IL-6 and IL-12.

This flood, or storm, of cytokines causes the tissue damage that occurs in autoinflammatory diseases including type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases such as Crohn’s disease. For some people with these conditions, ongoing inflammation also increases their risk of developing cancer.

Pasare and colleagues worked for the last 10 years to examine the genetic activity and cell-to-cell communications occurring behind this process. Together with their collaborators, the team found a surprising clue when examining the transcriptional profile of dendritic cells  following their interaction with T_EM cells. Specifically, they detected upregulation of expression of Tmem173, which encodes for stimulator of interferon genes (STING). The STING pathway has been described in previous research as being important to detect viral infections. But when T_EM cells harm dendritic cells, the STING pathway does not follow the same route that it typically does when directly responding to viral infections. The results of their tests, they noted, “suggested an alternate, non-canonical role of STING during T_EM cell-induced innate inflammation.”

In this situation, they found, STING teams up with the gene TRAF6 and the transcription factor NFkB to form an “axis” of activity that drives runaway production of innate inflammatory cytokines. The researchers further reasoned that if they could prevent STING and TRAF6 from working together, they could cut off the inflammation chain reaction at an early stage. In mice gene-edited to lack the STING pathway, that’s exactly what they found. When treated with a drug known to induce an intense T cell-mediated inflammatory response, these animals did not produce a flood of innate cytokines. The findings from a collective in vivo, as well as in vitro studies, provided what the authors suggested is “compelling evidence to establish STING as a major driver of T cell-induced inflammation in DCs, and these results have important implications for targeting STING for autoimmune and autoinflammatory diseases.”

The mouse study involved a whole-body elimination of STING. Attempting the same in humans would not be advisable because STING is used by a number of cell types outside the immune system in necessary ways, Pasare acknowledged. “STING is a widely expressed protein, and its diverse functional roles in multiple cell types pose a challenge for therapeutic targeting,” the team stated. Nevertheless, they suggested, “The discovery of T_EM cell-induced innate inflammation through DNA damage and a non-canonical STING-NF-kB pathway presents this pathway as a potential target to alleviate T cell-driven inflammation in autoimmunity and cytokine storms … It would be especially beneficial to preserve the anti-viral activity of STING and specifically target its ability to complex with TRAF6 to prevent TEM cell-induced inflammation.”

With a pathway defined, the next steps will include further study to confirm whether medications that target key points along the pathway can disrupt the inflammation cycle before it becomes uncontrollable, Pasare suggested. “The discovery of T_EM cell-induced innate inflammation through DNA damage and a non-canonical STING-NF-kB pathway presents this pathway as a potential target to alleviate T cell-driven inflammation in autoimmunity and cytokine storms,” the authors noted. “Our goal will be to develop a highly focused method or methods for blocking STING within targeted immune cells, without disrupting its other important functions. If we can achieve that, we may have a powerful new tool for controlling hyper-inflammation,” Pasare said.

Cincinnati Children’s co-authors on the reported study included first author Hannah Meibers, PhD, together with Kathrynne Warrick, Andrew VonHandorf, PhD, Charles Vallez, Kiana Kawarizadeh, Irene Saha, PhD, Omer Donmez, Viral Jain, MD, (now with the University of Alabama at Birmingham), Leah Kottyan, PhD, and Matthew Weirauch, PhD.

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The findings are published in the Proceedings of the National Academy of Sciences in an article titled “Loss of Pde1 function acts as an evolutionary gateway to penicillin resistance in Streptococcus pneumoniae.”

The new research has identified a genetic scar left in the genomes of bacteria as they become resistant to antibiotic treatment. The Sheffield team discovered mutations called pde1 act as an evolutionary gateway through which the S. pneumoniae cells start to become resistant to antibiotics.

Lead author, Andrew Fenton, PhD, from the School of Biosciences at the University of Sheffield, said: “Pneumonia is a dangerous and deadly infection and effective treatment with antibiotics is essential for patient care. However, the effectiveness of antibiotics is increasingly under threat as the bacteria which cause pneumonia become resistant to antibiotic treatment over time.

“This research has identified a genetic scar left in the genomes of bacteria as they become resistant to antibiotic treatment. This is a major step forward in understanding how resistance occurs and how we might be able to predict it.

“If we understand the emergence of antibiotic resistance then we can predict what groups of bacterial strains are becoming more dangerous. Giving us time to put control measures in place to stop their spread, saving patients’ lives.”

Over the last 10 years, there have been many large-scale genome association and genetic studies focused on S. pneumoniae antibiotic resistance but these have, so far, not led to effective mitigations.

The finding is a step forward in the molecular understanding of resistance and adds pde1 to the select few mutations known to promote antibiotic resistance in S. pneumoniae.

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Now, a previously uncharacterized adhesin protein specific to C. auris has been found to play a crucial role in the fungus’s ability to colonize a variety of living and non-living surfaces, and in its virulence.

This work is published in Science in the paper, “A Candida auris–specific adhesin, SCF1, governs surface association, colonization, and virulence.”

“These findings offer insight into the genetics and molecular mechanisms by which [this fungus] mediates surface association, a trait critical to the increasing disease burden of this emerging pathogen,” wrote the authors.

Since its discovery, C. auris has become increasingly responsible for life-threatening infections in healthcare facilities worldwide. Outbreaks of the multidrug-resistant pathogen are usually characterized by persistent colonization of patient skin and abiotic surfaces, including those of medical devices, which can remain positive for long periods and become intractable sources of contaminative transmission. This ability to colonize a wide range of surfaces is central to its emergence as a concerning threat to global health.

For fungal pathogens to attach to and colonize a surface, they rely on cell surface-exposed adhesin proteins. Although C. auris encodes genes similar to conserved adhesin families found in other Candida species, it’s unclear what gives C. auris its unique ability to colonize long-term on such a wide range of biotic and abiotic surfaces.

In this study, researchers characterized adhesins produced by C. auris and explored the basis of adhesion across 23 isolates from all five clades of the species.

In addition to conserved adhesins resembling those in other Candida species, they discovered a previously uncharacterized adhesin—Surface Colonization Factor (SCF1)—which was dominant and specific to C. auris. Unlike other fungal adhesins, which function through hydrophobic interactions, SCF1 relies on cationic interactions for surface attachment.

More specifically, the authors noted that SCF1 adheres “by cation-dependent interactions to a wide range of biotic and abiotic surfaces. Together with a complementary Candida adhesin, IFF4109, which attaches by hydrophobic interactions, these adhesins mediate colonization and biofilm formation.”

The authors showed that SCF1, in addition to the conserved adhesin IFF4109, are the principal mediators of biofilm formation, long-term surface colonization of skin and medical devices, and virulence in systemic infection.

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