Tag Archives: Chronic

Mouse study offers clues to developing an effective vaccine for Klebsiella bacteria

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A mouse study at Washington University School of Medicine in St. Louis points to data that could be key to developing an effective vaccine for the bacterium Klebsiella pneumoniae. The bug is often resistant to antibiotics, making it difficult to treat in some.

In the U.S., the bacterium Klebsiella pneumoniae is a common cause of urinary tract infection, bloodstream infection and pneumonia. While infections with the bacterium can be easily treated in some, Klebsiella has a dangerous flip side: It also is frequently resistant to antibiotics, making it extraordinarily difficult to treat in others. About half of people infected with a hypervirulent, drug-resistant strain of the bacterium die.

Scientists are working on vaccines for Klebsiella, but the optimal vaccine design is still unknown. However, a new study in mice by scientists at Washington University School of Medicine in St. Louis and Omniose, a St. Louis startup company specializing in vaccine production, provides critical data that could be key to developing an effective vaccine for Klebsiella. The findings, published in PLoS Pathogens, are a step toward taming the superbug.

When you think about the bugs that can be resistant to almost all antibiotics — the scary superbugs in the news — a lot of them are strains of Klebsiella. For a long time, the bacterium wasn’t even a pressing issue. But now it is, due to an explosion in antibiotic-resistant Klebsiella. Our goal is to diminish Klebsiella’s superbug status by developing a vaccine before hypervirulent or resistant strains sicken and kill even more people.”

David A. Rosen, MD, PhD, study’s senior author, assistant professor of pediatrics and of molecular microbiology at Washington University

Hypervirulent Klebsiella strains have spread globally, often causing community-acquired infections.

In the U.S., Klebsiella infections primarily occur in health-care facilities where medically vulnerable patients are immunocompromised, require long courses of antibiotics to treat other conditions, have chronic diseases, or are elderly people or newborns. “But now we’re seeing the emergence of hypervirulent strains dangerous enough to cause serious disease or death among healthy people in the community,” Rosen said.

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Most concerning among scientists are the strains of Klebsiella impervious to carbapenems, a class of broad-spectrum antibiotics used to treat the most severe bacterial infections. For this reason, the World Health Organization and the U.S. Centers for Disease Control and Prevention have identified carbapenem-resistant Klebsiella as an urgent threat to public health.

The rod-shaped bacterium is immobile and, like chocolate-covered candies, encapsulated in sugar coatings. In the new study, researchers created two experimental vaccines based on two different sugars, or polysaccharides, on Klebsiella’s surface: the terminal sugars on lipopolysaccharide, called O-antigen, and a capsular polysaccharide, or K-antigen. Since sugars by themselves tend to produce weak immune responses, the researchers linked each of the sugars to a protein to boost the immune response, creating so-called conjugate vaccines. Sugar-protein conjugate vaccines have proven successful in combating several bacteria including Streptococcus pneumoniae, the most common cause of pneumonia. Historically, this connection between the sugar and protein carrier has been achieved using synthetic chemistry in a test tube; however, the vaccines created for this study are called bioconjugate vaccines, because the researchers connected the sugar to the protein all within an engineered bacteria system.

Once the vaccines were created, the researchers tested the experimental bioconjugate vaccines’ ability to protect mice from disease caused by Klebsiella.

“It turned out that the capsule vaccine was far superior to the O-antigen vaccine,” said the study’s first author, Paeton Wantuch, PhD, a postdoctoral associate in Rosen’s lab. “Mice that received the capsule vaccine were significantly more likely to survive Klebsiella infection in their lungs or their bloodstream than mice that received the O-antigen vaccine.”

Both vaccines elicited high levels of antibodies against their respective targets. But the antibodies against the O-antigen just weren’t as effective as the ones against the capsule. In some strains of Klebsiella, the O-antigen may be obscured by other sugars, so the antibodies that target the O-antigen cannot make contact with their target.

“Our findings suggest that we may also need to include the capsule-based antigens in vaccine formulations developed against Klebsiella,” Rosen said. “This is why it’s so important for us to continue studying antibody-antigen interactions in the different strains, with the goal of identifying the ideal vaccine composition for clinical trials soon. The need has never been more imperative, especially as Klebsiella’s drug-resistant, hypervirulent strains become stronger, bolder and more dangerous to human health.”

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Source:
Journal reference:

Wantuch, P. L., et al. (2023) Area-deprivation, social care spending and the rates of children in care proceedings in local authorities in Engl Capsular polysaccharide inhibits vaccine-induced O-antigen antibody binding and function across both classical and hypervirulent K2:O1 strains of Klebsiella pneumoniae. PLOS Pathogens. doi.org/10.1371/journal.ppat.1011367.

Study may provide new avenues for addressing somatosensory symptoms of long COVID

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COVID-19, the disease resulting from SARS-CoV-2 infection, is associated with highly variable clinical outcomes that range from asymptomatic disease to death. For those with milder infections, COVID-19 can produce respiratory infection symptoms (cough, congestion, fever) and sensory phenotypes such as headache and loss of sense of smell. In more severe cases, SARS-CoV-2 infection can affect nearly every organ and result in strokes from vascular occlusion, cardiovascular damage and acute renal failure. A substantial number of actively infected patients suffering from both mild and severe infections experience sensory-related symptoms, such as headache, visceral pain, Guillain-Barre syndrome, nerve pain and inflammation. In most patients these symptoms subside after the infection ends, but, for other patients, they can persist.

In a new study, researchers from Boston University Chobanian & Avedisian School of Medicine, Icahn School of Medicine at Mount Sinai (Icahn Mount Sinai) and New York University (NYU), have found that thousands of genes were affected by SARS-CoV-2-mediated disease even after the viral infection had been cleared. These genes were associated with neurodegeneration and pain-related pathways, suggesting lasting damage to dorsal root ganglia (spinal nerves that carry sensory messages from various receptors) that may underlie symptoms of Post-Covid Conditions also known as Long Covid.

Several studies have found that a high proportion of Long Covid patients suffer from abnormal perception of touch, pressure, temperature, pain or tingling throughout the body. Our work suggests that SARS-CoV-2 might induce lasting pain in a rather unique way, emphasizing the need for therapeutics that target molecular pathways specific to this virus.”

Venetia Zachariou, PhD, corresponding author, chair of pharmacology, physiology & biophysics at BU Chobanian & Avedisian School of Medicine

This work was performed in collaboration with Benjamin tenOever, PhD, professor of microbiology and medicine at NYU, formerly at Icahn Mount Sinai.

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Using an experimental model infected with SARS-CoV-2, the researchers studied the effects of infection on sensitivity to touch, both during active infection and well after the infection had cleared. They then compared the effects of SARS-CoV-2 to those triggered by influenza A virus infection. In the experimental model, they observed a slow but progressive increase in sensory sensitivity over time – one that differed substantially from viral control, influenza A virus, which caused quick hypersensitivity during active infection but returned to normal by the time infection was over.

According to the researchers, this model can be used to gain information on genes and pathways affected by SARS-CoV-2, providing novel information to the scientific community on gene expression changes in sensory ganglia several weeks after infection.

“We hope this study will provide new avenues for addressing somatosensory symptoms of long COVID and ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome), which are only just now beginning to be addressed by mainstream medicine. While we have begun using this information by validating one promising target in this study, we believe our now publicly available data can yield insights into many new therapeutic strategies,” adds Zachariou.

These findings appear online in the journal Science Signaling.

This study was supported by National Institute of Neurological Disorders and Stroke NS086444S1 (R.A.S), the Zegar Family Foundation (B.T.) and the Friedman Brain Institute Research Scholars Program (V.Z., B.T., R.A.S., J.J.F.).

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Source:
Journal reference:

Serafini, R. A., et al. (2023) SARS-CoV-2 airway infection results in the development of somatosensory abnormalities in a hamster model. Science Signaling. doi.org/10.1126/scisignal.ade4984.

Study reveals how immune system protects the body against pathogens

First study of humans with a rare immunodeficiency reveals how the immune system protects the body against pathogens known to cause serious diseases, such as tuberculosis and COVID-19. The research involving McGill University, paves the way for new therapies to treat autoimmune diseases, chronic inflammatory diseases, and new approaches to vaccine development.

The immune system responds differently to various types of pathogens, like bacteria, parasites, and viruses. However, scientists are still trying to uncover how this complex network functions together and the processes that can go wrong with immunodeficiencies.

“The immune system plays a vital role in protecting the body from harmful germs that make people ill. It’s made up of a complex network of organs, cells, and proteins – like IRF1 or regulatory factor 1, which is key in the regulation of an early immune response to pathogens,” says co-author of the study David Langlais, an Assistant Professor in the Departments of Human Genetics and Microbiology and Immunology at McGill University.

“A better understanding of these specific processes will help us pinpoint the cause of defective immune responses, and perhaps even allow to boost an appropriate immune response to better combat illness,” adds Langlais who is also a Principal Investigator at the Victor Phillip Dahdaleh Institute of Genomic Medicine.

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Understanding the role of IRF1 in immune responses

Previous studies on mice that were IRF1 deficient have shown that the animals were highly susceptible to many viruses. In studying the first human patients with IRF1 deficiency ever identified, the researchers found that while the patients were highly susceptible to some bacterial infections, surprisingly they can defend themselves normally against viruses, including COVID-19.

This study provides new insight into the mechanisms underlying the human immune responses to mycobacteria, which includes pathogens known to cause tuberculosis, versus differences in the immune response to viruses. Unlike in mice, we show that in humans, the activity of IRF1 is not essential to anti-viral immunity.”

Jörg Fritz, Co-Author, Associate Professor in the Department of Microbiology and Immunology

“Based on our findings, it could be possible to think of therapeutic avenues to block or activate the action of IRF1 and control the type and intensity of immune responses. Our findings shed light on our understanding of the specificity and selectivity of our immune responses towards different pathogens,” says co-author Philippe Gros, a Professor in the Department of Biochemistry and Principal Investigator at the Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill.

Source:
Journal reference:

Rosain, J., et al. (2023). Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria. Cell. doi.org/10.1016/j.cell.2022.12.038.

Anticoronavirals: the development of COVID-19 therapies and the challenges that remain

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In a recent article published in Nature Microbiology, researchers highlighted the pace of development of coronavirus disease 2019 (COVID-19) therapies during the pandemic and the challenges that hinder the widespread availability of anticoronavirals.

Study: Therapeutics for COVID-19. Image Credit: Viacheslav Lopatin/Shutterstock.com
Study: Therapeutics for COVID-19. Image Credit: Viacheslav Lopatin/Shutterstock.com

Background

COVID-19 is the third coronavirus disease in the past 20 years after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). While the two predecessors caused severe mortality, they did not cause a pandemic. On the contrary, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered a pandemic, and by 21 February 2023, it had caused more than 757 million confirmed cases, including >6.8 million deaths worldwide.

Vaccines and monoclonal antibody (mAb) treatments for COVID-19 became available within a year of the pandemic. Yet, there is a substantial need for more effective therapeutics to treat unvaccinated and immunocompromised patients and those whose vaccine immunity waned over time.

About the study

In this study, the authors highlighted four stages of SARS-CoV-2 infection that require different therapeutic interventions as critical for identifying COVID-19 therapeutic targets. At stage 1, when viral replication begins inside the host, oral or intravenous administration of monoclonal antibodies and antiviral therapies are effective. However, an ideal time for prophylactic administration of vaccines is Stage 0 preceding the infection.

Clinical trials have established that mAbs and antivirals effectively combat COVID-19 when administered up to 10 days after symptom onset and within three to five days following the onset of symptoms, respectively. COVID-19 patients in stage 2 develop viral pneumonia, cough and fever, lung inflammation causing shortness of breath, and lung aberrations, such as ground glass opacities.

The most serious is stage 3 characterized by a hyperinflammatory state or acute respiratory distress syndrome (ARDS). Some patients might also develop coagulation disorders or shock or systemic inflammatory response syndrome (SIRS). Thus, at stage 3, a patient needs antiviral drugs and immunomodulatory therapy.

Stage 4 represents post-COVID-19 conditions when patients experience hyperinflammatory illnesses, e.g., multi-system inflammatory syndrome in children (MISC), following acute SARS-CoV-2 infection. Unfortunately, possible preventative measures and treatment for post-acute sequelae of SARS-CoV-2 (PASC) are not fully understood. It is a growing area of unmet medical need; thus, extensive research efforts are ongoing to classify PASC, which might be a conglomeration of several syndromes, and determine its cause(s).

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The National Institutes of Health (NIH) Treatment Guidelines Panel makes recommendations for the treatment and prevention of COVID-19. Early in the pandemic, clinicians used azithromycin and hydroxychloroquine as a possible COVID-19 treatment for hospitalized patients based on in vitro evidence of their synergistic effect on SARS-CoV-2 infection. Later, clinical trials found this combination ineffective. Similarly, the NIH panel did not specify recommendations for empirical antimicrobials.

The NIH rejected giving vitamin/mineral supplements, e.g., zinc, for hospitalized COVID-19 patients. On the contrary, they recommended prompt use of supplemental oxygenation and high-flow nasal cannula in patients with ARDS. In the absence of effective treatments, clinical recommendations by NIH continue to change and evolve.

Early drug repurposing efforts targeted nucleotide prodrugs, e.g., remdesivir (or GS-5734), AT-527, favipiravir, and molnupiravir (or MK-4482). However, only three antivirals received full Emergency Use Authorization (EUA) approval from the United States Food and Drug Administration (US-FDA), remdesivir, molnupiravir, and nirmatrelvir.

Pre-clinical characterization of remdesivir for other coronaviruses, pharmacokinetic and safety evaluation in humans in a failed clinical trial for Ebola virus, all acquired before the beginning of the COVID-19 pandemic, enabled rapid progression of remdesivir.

A phase 3 study conducted among patients in outpatient facilities and nursing facilities showed that remdesevir administration within seven days of symptom onset decreased hospitalization risk by 87%. Thus, its approval extended to high-risk non-hospitalized patients as well. Currently, phase 1b/2a study for inhaled remdesivir, and pre-clinical evaluation of an oral prodrug based on remdesivir is ongoing.

Another randomized phase III trial evaluated ivermectin, metformin, and fluvoxamine, all repurposed drug candidates, for early COVID-19 treatment of overweight or obese adults. Earlier pivotal efficacy and clinical studies found that molnupiravir provided no clinical benefit in hospitalized COVID-19 patients.

Conversely, the MOVe-OUT outpatient study demonstrated that treatment initiated within five days of symptom onset reduced the hospitalization risk or death. Accordingly, molnupiravir attained an EUA in the US on in late 2021 for treatment of mild-to-moderately ill COVID-19 patients at high risk of progression to severe disease. However, an outpatient study suggested that molnupiravir might augment SARS-CoV-2 evolution in immunocompromised individuals.

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In the USA, multiple initiatives have been undertaken to identify candidate agents that may be repurposed as COVID-19 drugs. For instance, the Bill and Melinda Gates Foundation launched the Therapeutics Accelerator in March 2020, wherein they adopted a three-way approach to test approved drugs, screen drug repositories, and evaluate novel small molecules, including mAbs against SARS-CoV-2.

Encouragingly, apilimod, a PIKfyve kinase inhibitor developed for treating autoimmune diseases, is being tested for COVID-19 in clinical studies. Likewise, multiple clinical trials are ongoing for camostat mesilate, an inhibitor of transmembrane protease serine 2 (TMPRSS2), an approved chronic pancreatitis treatment in Japan.

Among anti-inflammatory and immunomodulating drugs, dexamethasone, a corticosteroid, baricitinib, a Janus kinase (JAK) inhibitor, and tocilizumab have received FDA approval. Among mAb therapies, casirivimab with imdevimab and bamlanivimab with etesevimab, Sotrovimab, Bebtelovimab, Tixagevimab–cilgavimab have received FDA approval. However, as SARS-CoV-2 continues to evolve, changes in the spike protein led to EUAs being withdrawn for all mAb therapies due to loss of efficacy.

Conclusions

There is a vast knowledge gap regarding COVID-19 pathogenesis. Despite the absence of a viral reservoir, severe disease persists for weeks or even months after COVID-19 recovery. Another intriguing area of investigation is why autoantibodies increase over time during COVID-19. In February 2022, the government of the United States of America (USA) started a flagship program, RECOVER, to understand, prevent and treat COVID-19-related long-term health effects.

Amid decreasing vaccine uptake and waning efficacy of mAbs as SARS-CoV-2 mutates, there is a need for new, safe, and effective COVID-19 therapies for population-level deployment and the potential to reduce resistance development. Researchers need to accelerate research targeting small molecule candidates that would mechanistically target the conserved region of SARS-CoV-2 and not become ineffective across mutant strains.

To be prepared for another pandemic, a large repository of small molecules that have already progressed through early pre-clinical and clinical evaluation is needed to develop drugs, like remdesivir, developed in a short span of two years.

More importantly, research efforts should continue to advance the development of antivirals for other pathogens, including coronaviruses, in preparation for the next pandemic.

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Journal reference:

University Hospital Bonn coordinates eWHORM project to combat worm infections in sub-Saharan Africa

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African and European partners join forces to enable the World Health Organisation’s (WHO) “Road Map for Neglected Tropical Diseases” (NTDs) and reduce the burden of disease associated with worm infections.

Worm infections (helminthiases) affect around 1.5 billion people worldwide, making them one of the most prevalent infections in humans. Parasitic worms (helminths) are often transmitted through insect bites or contaminated soil in areas with limited access to clean water, sanitation, and healthcare. These infections can cause chronic and debilitating health problems, such as lymphatic filariasis, onchocerciasis (river blindness), loiasis (African eye worm), mansonellosis, and trichuriasis (whipworm infection).

To combat various soil-transmitted helminths (STH) and filarial worms, a new multidisciplinary consortium of research institutes, universities and not-for-profit organisations in sub-Saharan Africa (SSA) and Europe, coordinated by the University Hospital Bonn (UKB) in Germany, will work together to establish a new adaptive clinical trial platform and improve the clinical research infrastructure in several SSA countries. While each partner will bring unique know-how and complementary experience to achieve the project’s objectives, strong representation from the Global South will drive eWHORM activities. eWHORM will be funded with EUR 7.9 million from the European Union’s European and Developing Countries Clinical Trials Partnership (EDCTP3) programme and additional EUR 3.4 million from the Swiss Government over the next five years.

Achieving the ambitious WHO Road Map goals

Despite significant progress in preventing and controlling helminthiases, many existing drugs have proven problematic in terms of efficacy, treatment duration, and safety. In addition, the chronic underinvestment in healthcare in developing countries has led to poor infrastructure and inadequately trained technical staff.

The eWHORM project aims to address these issues by further developing and testing more efficacious and safe treatment options that act across different helminth species. The project will also train healthcare professionals to enable the diagnosis of multiple diseases in four endemic countries: the Democratic Republic of the Congo, the Gabonese Republic, the Republic of Cameroon, and the United Republic of Tanzania.

This major leap will help to achieve two pressing WHO objectives: (1) eliminating filarial and STH infections and (2) building capacity in endemic countries.

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Responding to persisting and future health challenges

Establishing a robust and equitable clinical research infrastructure is crucial to sustaining the progress that will be brought about by eWHORM. To this end, project partners will promote research network building, knowledge exchange, skill sharing, and gender equality awareness. Early career scientists in SSA will be supported through a Master’s and PhD programme, mentorship programme, and dedicated webinars on all aspects of clinical trial conduct and research. This will, in turn, increase effectiveness and preparedness for both current and future health crises and ensure equitable access to treatment, care, and support for all patients.

Cutting-edge clinical trial to end multiple neglected tropical diseases

The broad-spectrum helminth-killing (pan-nematode anthelmintic) drug oxfendazole (OXF) is used since several decades in the veterinary field to treat multiple species of helminths safely and effectively. In the recent drug development initiative “Helminth Elimination Platform” (HELP), a field-applicable formulation of the cost-effective and easy-to-manufacture drug OXF was developed and a bioavailability study was performed in humans. Several partners, who worked towards a superior, pan-nematode anthelmintic in HELP, are now continuing their ground-breaking research in eWHORM.

Our mission in eWHORM is to assess the efficacy of OXF for simultaneous evaluation against onchocerciasis, loiasis, mansonellosis, and trichuriasis. To do this, we plan to set up a state-ofthe-art adaptive basket trial that can test OXF against multiple diseases at once. This will help us to quickly find out if OXF works and get it to patients faster.”

Marc Hübner, project coordinator, professor of translational microbiology at the Institute for Medical Microbiology, Immunology and Parasitology (IMMIP) at the University Hospital Bonn

“The Drugs for Neglected Diseases initiative (DNDi) and Dr. Sabine Specht, Head of Filarial Disease at DNDi, have a long-standing track record in developing and enabling access to more effective and affordable drugs for Neglected Tropical Diseases,” adds Hübner. “Together with some of the most eminent research and development partners and national stakeholders worldwide, we are looking forward to contributing to what can generate a profound change in the treatment and elimination of helminth diseases.”

Next to the University of Buea, the Centre de Recherches Médicales de Lambaréné, and the Institut National de Recherche Biomédicale, the consortium includes experts from the Bernhard-Nocht-Institute for Tropical Medicine, the Medical University of Vienna, the Erasmus University Medical Center, the Swiss Tropical and Public Health Institute and Eurice – European Research and Project Office GmbH.

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Study expands the knowledge about gut viral diversity in healthy infants

Viruses are usually associated with illness. But our bodies are full of both bacteria and viruses that constantly proliferate and interact with each other in our gastrointestinal tract. While we have known for decades that gut bacteria in young children are vital to protect them from chronic diseases later on in life, our knowledge about the many viruses found there is minimal.

A few years back, this gave University of Copenhagen professor Dennis Sandris Nielsen the idea to delve more deeply into this question. As a result, a team of researchers from COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) and the Department of Food Science at UCPH, among others, spent five years studying and mapping the diaper contents of 647 healthy Danish one-year-olds.

“We found an exceptional number of unknown viruses in the feces of these babies. Not just thousands of new virus species – but to our surprise, the viruses represented more than 200 families of yet to be described viruses. This means that, from early on in life, healthy children are tumbling about with an extreme diversity of gut viruses, which probably have a major impact on whether they develop various diseases later on in life,” says Professor Dennis Sandris Nielsen of the Department of Food Science, senior author of the research paper about the study, now published in Nature Microbiology.

The researchers found and mapped a total of 10,000 viral species in the children’s feces – a number ten times larger than the number of bacterial species in the same children. These viral species are distributed across 248 different viral families, of which only 16 were previously known. The researchers named the remaining 232 unknown viral families after the children whose diapers made the study possible. As a result, new viral families include names like Sylvesterviridae, Rigmorviridae and Tristanviridae.

Bacterial viruses are our allies

This is the first time that such a systematic an overview of gut viral diversity has been compiled. It provides an entirely new basis for discovering the importance of viruses for our microbiome and immune system development. Our hypothesis is that, because the immune system has not yet learned to separate the wheat from the chaff at the age of one, an extraordinarily high species richness of gut viruses emerges, and is likely needed to protect against chronic diseases like asthma and diabetes later on in life.”

Shiraz Shah, first author and senior researcher at COPSAC

Ninety percent of the viruses found by the researchers are bacterial viruses – known as bacteriophages. These viruses have bacteria as their hosts and do not attack the children’s own cells, meaning that they do not cause disease. The hypothesis is that bacteriophages primarily serve as allies:

“We work from the assumption that bacteriophages are largely responsible for shaping bacterial communities and their function in our intestinal system. Some bacteriophages can provide their host bacterium with properties that make it more competitive by integrating its own genome into the genome of the bacterium. When this occurs, a bacteriophage can then increase a bacterium’s ability to absorb e.g. various carbohydrates, thereby allowing the bacterium to metabolize more things,” explains Dennis Sandris Nielsen, who continues:

“It also seems like bacteriophages help keep the gut microbiome balanced by keeping individual bacterial populations in check, which ensures that there are not too many of a single bacterial species in the ecosystem. It’s a bit like lion and gazelle populations on the savannah.”

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Shiraz Shah adds:

“Previously, the research community mostly focused on the role of bacteria in relation to health and disease. But viruses are the third leg of the stool and we need to learn more about them. Viruses, bacteria and the immune system most likely interact and affect each other in some type of balance. Any imbalance in this relationship most likely increases the risk of chronic disease.”

The remaining ten percent of viruses found in the children are eukaryotic – that is, they use human cells as hosts. These can be both friends and foes for us:

“It is thought-provoking that all children run around with 10-20 of these virus types that infect human cells. So, there is a constant viral infection taking place, which apparently doesn’t make them sick. We just know very little about what’s really at play. My guess is that they’re important for training our immune system to recognise infections later. But it may also be that they are a risk factor for diseases that we have yet to discover,” says Dennis Sandris Nielsen.

Could play an important role in inflammatory diseases

The researchers have yet to discover where the many viruses in the one-year-olds come from. Their best answer thus far is the environment:

“Our gut is sterile until we are born. During birth, we are exposed to bacteria from the mother and environment. It is likely that some of the first viruses come along with these initial bacteria, while many others are introduced later via dirty fingers, pets, dirt that kids put in their mouths and other things in the environment,” says Dennis Sandris Nielsen.

As Shiraz Shah points out, the entire field of research speaks to a huge global health problem:

“A lot of research suggests that the majority of chronic diseases that we’re familiar with – from arthritis to depression – have an inflammatory component. That is, the immune system is not working as it ought to – which might be because it wasn’t trained properly. So, if we learn more about the role that bacteria and viruses play in a well-trained immune system, it can hopefully lead us to being able to avoid many of the chronic diseases that afflict so many people today.”

The research groups have begun investigating the role of gut viruses in relation to a number of different diseases that occur in childhood, such as asthma and ADHD.

Source:
Journal reference:

Shah, S. A., et al. (2023). Expanding known viral diversity in the healthy infant gut. Nature Microbiology. doi.org/10.1038/s41564-023-01345-7.

Research finds SARS-CoV-2 Omicron variant to be more fatal than seasonal influenza

Adults hospitalized with the SARS-CoV-2 Omicron variant have a higher death rate than those hospitalized with seasonal influenza, even though Omicron is considered less virulent with lower case fatality rates than the delta and alpha strains, new research being presented at this year’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Copenhagen, Denmark (15-18 April) suggests.

The study by Dr Alaa Atamna and colleagues from the Rabin Medical Center at Belinison Hospital in Israel found that adults (18 years or older) hospitalized with influenza were 55% less likely to die within 30 days than those hospitalized with Omicron during the 2021-2022 influenza season.

Influenza and COVID-19 are both respiratory diseases with similar modes of transmission. In December 2021, influenza re-emerged in Israel after it went undetected since March 2020. At the same time, the Omicron had substituted Delta as the predominant variant. But data directly comparing Omicron with seasonal influenza are scarce.

To find out more, researchers compared the clinical outcomes of patients hospitalized with COVID-19 (Omicron variant) and those hospitalized with influenza at a large academic hospital in Israel.

Consecutive patients hospitalized with laboratory confirmed COVID-19 (167 patients; average age 71 years, 58% male) and influenza infection (221 patients; average age 65 years, 41% male) during December 2021 and January 2022 were included in the study.

Overall, 63 patients died within 30 days-;19 (9%) admitted with influenza and 44 (26%) hospitalized with Omicron.

Patients with Omicron tended to have higher overall comorbidity scores, needed more assistance performing activities of daily living (e.g., washing and dressing), and were more likely to have high blood pressure and diabetes, whereas asthma was more common in those hospitalized with influenza (see table 1 in notes to editors).

Respiratory complications and need for oxygen support and mechanical ventilation were also more common in Omicron cases than in seasonal influenza.

A possible reason for the higher Omicron death rate is that patients admitted with Omicron were older with additional major underlying illnesses such as diabetes and chronic kidney disease. The difference might also be due to an exaggerated immune response in COVID-19, and that vaccination against COVID-19 was far lower among patients with Omicron.”

Dr Alaa Atamna, Rabin Medical Center at Belinison Hospital in Israel

He continues, “The double whammy of overlapping influenza and COVID-19 epidemics will increase the complexity of disease and the burden on health systems. There is one basic step people can take that may alter the trajectory of either epidemic, get the vaccines for flu and COVID-19, especially if you are older and have underlying illnesses.”

The authors point out that the study was observational so can’t prove causation, and it was conducted in one hospital in Israel so the results may not apply to other countries and populations. And they cannot rule out the possibility that other unmeasured factors such as influenza and COVID19 vaccination status may have influenced the results. They also note that the excess mortality observed for Omicron could be the result of an influenza season that was less severe than usual. Finally, the study included only hospitalized patients, so could not estimate the proportion of hospitalized patients in the total number of infected patients.

Research identifies western diet-induced microbial and metabolic contributors to liver disease

New research from the University of Missouri School of Medicine has established a link between western diets high in fat and sugar and the development of non-alcoholic fatty liver disease, the leading cause of chronic liver disease.

The research, based in the Roy Blunt NextGen Precision Health Building at MU, has identified the western diet-induced microbial and metabolic contributors to liver disease, advancing our understanding of the gut-liver axis, and in turn the development of dietary and microbial interventions for this global health threat.

We’re just beginning to understand how food and gut microbiota interact to produce metabolites that contribute to the development of liver disease. However, the specific bacteria and metabolites, as well as the underlying mechanisms were not well understood until now. This research is unlocking the how and why.”

Guangfu Li, PhD, DVM, co-principal investigator, associate professor in the department of surgery and Department of Molecular Microbiology and Immunology

The gut and liver have a close anatomical and functional connection via the portal vein. Unhealthy diets change the gut microbiota, resulting in the production of pathogenic factors that impact the liver. By feeding mice foods high in fat and sugar, the research team discovered that the mice developed a gut bacteria called Blautia producta and a lipid that caused liver inflammation and fibrosis. That, in turn, caused the mice to develop non-alcoholic steatohepatitis or fatty liver disease, with similar features to the human disease.

“Fatty liver disease is a global health epidemic,” said Kevin Staveley-O’Carroll, MD, PhD, professor in the department of surgery, one of the lead researchers. “Not only is it becoming the leading cause of liver cancer and cirrhosis, but many patients I see with other cancers have fatty liver disease and don’t even know it. Often, this makes it impossible for them to undergo potentially curative surgery for their other cancers.”

As part of this study, the researchers tested treating the mice with an antibiotic cocktail administered via drinking water. They found that the antibiotic treatment reduced liver inflammation and lipid accumulation, resulting in a reduction in fatty liver disease. These results suggest that antibiotic-induced changes in the gut microbiota can suppress inflammatory responses and liver fibrosis.

Li, Staveley-O’Carroll and fellow co-principal investigator R. Scott Rector, PhD, Director of NextGen Precision Health Building and Interim Senior Associate Dean for Research -; are part of NextGen Precision Health, an initiative to expand collaboration in personalized health care and the translation of interdisciplinary research for the benefit of society. The team recently received a $1.2 million grant from the National Institutes of Health to fund this ongoing research into the link between gut bacteria and liver disease.

Source:
Journal reference:

Yang, M., et al. (2023). Western diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol. Nature Communications. doi.org/10.1038/s41467-023-35861-1.

Host immune system forms small lesions in the intestines in response to bacterial infection

Yersinia bacteria cause a variety of human and animal diseases, the most notorious being the plague, caused by Yersinia pestis. A relative, Yersinia pseudotuberculosis, causes gastrointestinal illness and is less deadly but naturally infects both mice and humans, making it a useful model for studying its interactions with the immune system.

These two pathogens, as well as a third close cousin, Y. enterocolitica, which affects swine and can cause food-borne illness if people consume infected meat, have many traits in common, particularly their knack for interfering with the immune system’s ability to respond to infection.

The plague pathogen is blood-borne and transmitted by infected fleas. Infection with the other two depends on ingestion. Yet the focus of much of the work in the field had been on interactions of Yersinia with lymphoid tissues, rather than the intestine. A new study of Y. pseudotuberculosis led by a team from Penn’s School of Veterinary Medicine and published in Nature Microbiology demonstrates that, in response to infection, the host immune system forms small, walled-off lesions in the intestines called granulomas. It’s the first time these organized collections of immune cells have been found in the intestines in response to Yersinia infections.

The team went on to show that monocytes, a type of immune cell, sustain these granulomas. Without them, the granulomas deteriorated, allowing the mice to be overtaken by Yersinia.

“Our data reveal a previously unappreciated site where Yersinia can colonize and the immune system is engaged,” says Igor Brodsky, senior author on the work and a professor and chair of pathobiology at Penn Vet. “These granulomas form in order to control the bacterial infection in the intestines. And we show that if they don’t form or fail to be maintained, the bacteria are able to overcome the control of the immune system and cause greater systemic infection.”

The findings have implications for developing new therapies that leverage the host immune system, Brodsky says. A drug that harnessed the power of immune cells to not only keep Yersinia in check but to overcome its defenses, they say, could potentially eliminate the pathogen altogether.

A novel battlefield

Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica share a keen ability to evade immune detection.

“In all three Yersinia infections, a hallmark is that they colonize lymphoid tissues and are able to escape immune control and replicate, cause disease, and spread,” Brodsky says.

Earlier studies had shown that Yersinia prompted the formation of granulomas in the lymph nodes and spleen but had never observed them in the intestines until Daniel Sorobetea, a research fellow in Brodsky’s group, took a closer look at the intestines of mice infected with Y. pseudotuberculosis.

“Because it’s an orally acquired pathogen, we were interested in how the bacteria behaved in the intestines,” Brodsky says. “Daniel made this initial observation that, following Yersinia pseudotuberculosis infection, there were macroscopically visible lesions all along the length of the gut that had never been described before.”

The research team, including Sorobetea and later Rina Matsuda, a doctoral student in the lab, saw that these same lesions were present when mice were infected with Y. enterocolitica, forming within five days after an infection.

A biopsy of the intestinal tissues confirmed that the lesions were a type of granuloma, known as a pyogranuloma, composed of a variety of immune cells, including monocytes and neutrophils, another type of white blood cell that is part of the body’s front line in fighting bacteria and viruses.

Granulomas form in other diseases that involve chronic infection, including tuberculosis, for which Y. pseudotuberculosis is named. Somewhat paradoxically, these granulomas-;while key in controlling infection by walling off the infectious agent-;also sustain a population of the pathogen within those walls.

The team wanted to understand how these granulomas were both formed and maintained, working with mice lacking monocytes as well as animals treated with an antibody that depletes monocytes. In the animals lacking monocytes “these granulomas, with their distinct architecture, wouldn’t form,” Brodsky says.

Instead, a more disorganized and necrotic abscess developed, neutrophils failed to be activated, and the mice were less able to control the invading bacteria. These animals experienced higher levels of bacteria in their intestines and succumbed to their infections.

Groundwork for the future

The researchers believe the monocytes are responsible for recruiting neutrophils to the site of infection and thus launching the formation of the granuloma, helping to control the bacteria. This leading role for monocytes may exist beyond the intestines, the researchers believe.

We hypothesize that it’s a general role for the monocytes in other tissues as well.”

Igor Brodsky, senior author

But the discoveries also point to the intestines as a key site of engagement between the immune system and Yersinia.

“Previous to this study we knew of Peyer’s patches to be the primary site where the body interacts with the outside environment through the mucosal tissue of the intestines,” says Brodsky. Peyer’s patches are small areas of lymphoid tissue present in the intestines that serve to regulate the microbiome and fend off infection.

In future work, Brodsky and colleagues hope to continue to piece together the mechanism by which monocytes and neutrophils contain the bacteria, an effort they’re pursing in collaboration with Sunny Shin’s lab in the Perelman School of Medicine’s microbiology department.

A deeper understanding of the molecular pathways that regulate this immune response could one day offer inroads into host-directed immune therapies, by which a drug could tip the scales in favor of the host immune system, unleashing its might to fully eradicate the bacteria rather than simply corralling them in granulomas.

“These therapies have caused an explosion of excitement in the cancer field,” Brodsky says, “the idea of reinvigorating the immune system. Conceptually we can also think about how to coax the immune system to be reinvigorated to attack pathogens in these settings of chronic infection as well.”

Source:
Journal reference:

Sorobetea, D., et al. (2023). Inflammatory monocytes promote granuloma control of Yersinia infection. Nature Microbiology. doi.org/10.1038/s41564-023-01338-6.

Review on factors related to variations in human microbiota

In a recent review published in Current Opinion in Microbiology, researchers reviewed existing data on variations in human microbiota, emphasizing on ageing- and ethnicity-associated changes in the microbiota.

Study: Human microbiome variance is underestimated. Image Credit: Troyan/Shutterstock
Study: Human microbiome variance is underestimated. Image Credit: Troyan/Shutterstock

Background

Human microbial heterogeneity lays the foundation for precision therapeutics, and thus, the potential of personalized microbiota-based diagnostic and therapeutic strategies can be tapped fully by understanding human microbial variations. However, the factors associated with alterations in the human microbiome have yet to be well-characterized.

Further, most of the human microbiota data has been obtained from residents of westernized and socioeconomically developed nations, with the probable skewing of microbiota variations and their associations with health. Moreover, the under-sampling of ethnic minorities in microbiota analyses must be addressed for assessing the history, context, and evolving dynamics of the human microbiota in the context of disease risks.

About the review

In the present review, researchers highlighted recent advances in characterizing human microbiota variations associated with ageing and various ethnicities globally.

Age-related changes in the microbiota of humans

Factors that shape the human microbiota include birth type, family sizes, cohabitation, housing, domestic animals, age, sex, physical fitness, diet, antibiotics, non-antibiotic drugs, and alcohol intake. At the societal level, complex associations of health inequalities, socioeconomic status, and social networks with the human microbiome balance have been reported.

Studies have demonstrated an inverse association between the microbiota and an individual’s age, and conversely, microbial compositional variations contribute to the process of ageing and age-associated diseases. All individuals do not age uniformly, and the differential ageing rates reflect in the human microbiota. Therefore, the human microbiota abundance is evolving as a biomarker to evaluate differences in the biological age and chronological age and between health and disease. Human microbiomes lacking Bacteroides species have been strongly associated with a healthy type of ageing.

Other factors related to variations in the human microbiota composition

Mediterranean diets, involving reduced intake of saturated-type fats, red meat, and milk products, with high consumption of fruits, vegetables, fish, legumes, nuts, and olive oil, have been reported to reverse age-associated microbiota alterations and delay cognitive decline. Studies have reported the co-evolution of human beings and intestinal microbes, with notable variations in Helicobacter pylori diversity associated with human migration.

Microbiome compositions vary among individuals residing in industrialized or non-industrialized regions. Non-industrialized region-associated microbiomes or ancestral microbes have adapted to metabolizing complex-type carbohydrates from diets with high fibre content. The microbial compositions vary by season, climatic fluctuations, and accessibility to unprocessed-type foods. The microbiome of individuals living in non-industrialized regions reportedly has lower Bacteroides/Prevotella spp. ratio, elevated counts of Treponema species, and varying abundance of parasites that affect the immunity of the host.

Naturally maintained palaeofaeces microbiome genomes resemble the genomes of non-industrialized human intestinal microbiota. Socioeconomic developments and industrialization have been associated with microbiome diversity losses, lowered parasitism, reduced counts of ancestral microbes like Helicobacter pylori species and elevated counts of microbes associated with non-communicable and chronic metabolic and inflammatory diseases.

Immigration has been related to an increased abundance of microbes associated with obesity. A study on Irish travellers reported three key factors influencing the human microbiota composition, i.e., living conditions, closeness to domestic pets during childhood and family sizes, with the average number of siblings among traveller families and other families being 10, and one, respectively).

Conclusions

Based on the review findings, the human microbiome is influenced by age, diet, ethnicity and immigration. Further research is required to improve understanding of age-related microbiome changes to identify targets and develop tailored microbiota-based therapeutic interventions. The increase or decrease in microbial abundance associated with changes in dietary patterns and modernization needs to be assessed further to develop highly specific precision medicine catered to the residential locations and food consumed.

The co-diversification of microbes with humans globally warrants in-depth analysis of microbial compositions by ethnicity, region, diet, and industrialization status to maximize the benefit of microbiota-based interventions to one and all. Microbial analyses were performed to evaluate the risk of disease in relation to microbiome dysbiosis and abrupt changes following immigration could inform policy-makers and decision-making and aid in developing personalized therapeutics to improve the standard of care for all individuals across the globe.

Journal reference: