Category Archives: Microbiology

Microbiology

Fomepizole helps overcome antibiotic-resistant pneumonia in mice, study finds

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Pneumococcal disease leads to over three million hospitalizations and hundreds of thousands of deaths annually. A study publishing March 16 in the open access journal PLOS Biology by Carlos J. Orihuela at the University of Alabama at Birmingham, Alabama, United States, and colleagues suggests that the FDA-approved drug Fomepizole may reduce disease severity in the lungs of mice with some forms of bacterial pneumonia and enhance the efficacy of the antibiotic erythromycin as well.

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. While vaccines to protect against the bacteria are available, these vaccines are not effective against all strains, with some versions being especially problematic as they are multidrug-resistant. Currently, there are very limited treatment options for combating multidrug-resistant S. pneumoniae infections.

In order to test the effects of novel treatments for antibiotic-resistant S. pneumoniae, the researchers conducted a series of experiments with mice. Fomepizole is an FDA-approved drug normally used as an antidote for the ingestion of toxic alcohols (such as methanol or ethylene glycol), and works by inhibiting the enzyme alcohol dehydrogenase. Researchers inoculated mice with a multidrug-resistant S. pneumoniae and tested the effect of fomepizole in a combinatorial treatment with antibiotics. They quantified the bacterial burden in the organs of infected mice, comparing the experimental group with the control group.

The researchers found that using Fomepizole blocked normal energy production by S. pneumoniae and enhanced the bacteria’s susceptibility to antibiotics and reduced bacterial burden in the lungs of mice with pneumonia. The combination treatment was effective in preventing the development of invasive disease. Future research is needed however, as this novel drug treatment has not been replicated in clinical studies on humans, who may present with complicating factors such as comorbidities, advanced age, or environmental variables that may play a role in disease outcomes.

Orihuela adds, “Pharmacological targeting of fermentation pathways is a new way to enhance the susceptibility of some bacteriato antimicrobials. Combination treatment of erythromycin and fomepizole, an alcohol dehydrogenase inhibitor, prevented the in vivo dissemination of antibiotic-resistant Streptococcus pneumoniae.”

  • Hansol Im, Madison L. Pearson, Eriel Martinez, Kyle H. Cichos, Xiuhong Song, Katherine L. Kruckow, Rachel M. Andrews, Elie S. Ghanem, Carlos J. Orihuela. Targeting NAD+ regeneration enhances antibiotic susceptibility of Streptococcus pneumoniae during invasive disease. PLOS Biology, 2023; 21 (3): e3002020 DOI: 10.1371/journal.pbio.3002020

    • PLOS
    Microbiology

    Low-cost, universal oral COVID-19 vaccine prevents severe respiratory illness in hamsters

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    Reviewed by Emily Henderson, B.Sc.Mar 22 2023

    A UCLA-led team has developed an inexpensive, universal oral COVID-19 vaccine that prevented severe respiratory illness and weight loss when tested in hamsters, which are naturally susceptible to SARS-CoV-2. It proved as effective as vaccines administered by injection or intranasally in the research.

    If ultimately approved for human use, it could be a weapon against all COVID-19 variants and boost uptake, particularly in low- and middle-income countries, and among those with an aversion to needles.

    The study is published in the peer-reviewed journal Microbiology Spectrum.

    The oral vaccine is based primarily on the nucleocapsid protein, which is the most abundantly expressed of the virus’s four major structural proteins and evolves at a much slower rate than the frequently mutating spike protein. The vaccine utilizes a highly weakened bacterium to produce the nucleocapsid protein in infected cells as well as the membrane protein, which is another highly abundant viral structural protein.

    Being a universal vaccine based primarily upon the nucleocapsid protein, the vaccine is resistant to the incessant mutations of the SARS-CoV-2 spike protein upon which virtually all current vaccines are based. As a result, current vaccines rapidly become obsolete, requiring that they repeatedly be re-engineered. Hence, our vaccine should protect against new and emerging variants of SARS-CoV-2.”

    Dr. Marcus Horwitz, senior author, distinguished professor of medicine in the Division of Infectious Diseases and of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA

    Oral delivery also makes it easier to distribute the vaccine in resource poor areas of the world by eliminating the need for needles, syringes, and trained personnel to deliver injectable vaccines, he added. “An oral vaccine may also be attractive to many people with vaccine hesitancy on account of fear of needles.”

    The researchers noted that while it worked exceptionally well in preventing severe respiratory illness, it did not provide full protection against high viral loads in the hamsters. Also, they did not test it against the Omicron strain, which contains a nearly identical nucleocapsid protein, because of this strain’s low virulence in the golden Syrian hamsters they used.

    But the vaccine, they write, “is efficacious when administered via the oral route against COVID-19-like disease in a highly demanding animal model. This conveniently administered, easily manufactured, inexpensive, and readily stored and transported vaccine could play a major role in ending the COVID-19 pandemic by protecting immunized individuals from serious disease from current and future strains of SARS-CoV-2.”

    The next step in the process will be to manufacture the vaccine for oral administration via an acid-resistant enteric capsule that will allow the vaccine to be safely released in the small intestine, Horwitz said. It will then be tested for safety, immunogenicity, and efficacy in humans.

    “We also plan to expand the vaccine to protect against infections caused by other types of potentially pandemic coronaviruses such as the virus that causes Middle Eastern Respiratory Syndrome (MERS),” he added.

    Additional authors are Qingmei Jia and Saša Masleša-Galić of UCLA; Helle Bielefeldt-Ohmann of the University of Queensland, Australia; and Rachel Maison, Airn Hartwig, and Richard Bowen of Colorado State University.

    This study was supported by a Corona Virus Seed grant from the UCLA AIDS Institute and Charity Treks and by the National Institutes of Health (AI141390).

    Source:

    UCLA Health

    Journal reference:

    Jia, Q., et al. (2023). Oral Administration of Universal Bacterium-Vectored Nucleocapsid-Expressing COVID-19 Vaccine is Efficacious in Hamsters. Microbiology Spectrum. doi.org/10.1128/spectrum.05035-22.

    Microbiology

    Co-infection with MRSA ‘superbug’ could make COVID-19 outcomes even more deadly

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    Reviewed by Emily Henderson, B.Sc.Mar 21 2023

    Global data shows nearly 10 per cent of severe COVID-19 cases involve a secondary bacterial co-infection – with Staphylococcus aureus, also known as Staph A., being the most common organism responsible for co-existing infections with SARS-CoV-2. Researchers at Western have found if you add a ‘superbug’ – methicillin-resistant Staphylococcus aureus (MRSA) – into the mix, the COVID-19 outcome could be even more deadly.

    The mystery of how and why these two pathogens, when combined, contribute to the severity of the disease remains unsolved. However, a team of Western researchers has made significant progress toward solving this “whodunit”.

    New research by Mariya Goncheva, Richard M. Gibson, Ainslie C. Shouldice, Jimmy D. Dikeakos and David E. Heinrichs, has revealed that IsdA, a protein found in all strains of Staph A., enhanced SARS-CoV-2 replication by 10- to 15-fold. The findings of this study are significant and could help inform the development of new therapeutic approaches for COVID-19 patients with bacterial co-infections.

    Interestingly, the study, which was recently published in iScience, also showed that SARS-CoV-2 did not affect the bacteria’s growth. This was contrary to what the researchers had initially expected.

    We started with an assumption that SARS-CoV-2 and hospitalization due to COVID-19 possibly caused patients to be more susceptible to bacterial infections which eventually resulted in worse outcomes.”

    Mariya Goncheva

    Goncheva is a former postdoctoral associate, previously with the department of microbiology and immunology at Schulich School of Medicine & Dentistry.

    Goncheva said bacterial infections are most commonly acquired in hospital settings and hospitalization increases the risk of co-infection. “Bacterial infections are one of the most significant complications of respiratory viral infections such as COVID-19 and Influenza A. Despite the use of antibiotics, 25 per cent of patients co-infected with SARS-CoV-2 and bacteria, die as a result. This is especially true for patients who are hospitalized, and even more so for those in intensive care units. We were interested in finding why this happens,” said Goncheva, lead investigator of the study.

    Goncheva, currently Canada Research Chair in virology and professor of biochemistry and microbiology at the University of Victoria, studied the pathogenesis of multi-drug resistant bacteria (such as MRSA) supervised by Heinrichs, professor of microbiology and immunology at Schulich Medicine & Dentistry.

    When the COVID-19 pandemic hit, she pivoted to study interactions between MRSA and SARS-CoV-2.

    For this study, conducted at Western’s level 3 biocontainment lab, Imaging Pathogens for Knowledge Translation (ImPaKT), Goncheva’s work created an out-of-organism laboratory model to study the interactions between SARS-CoV-2 and MRSA, a difficult-to-treat multi-drug resistant bacteria.

    “At the beginning of the pandemic, the then newly opened ImPaKT facility made it possible for us to study the interactions between live SARS-CoV-2 virus and MRSA. We were able to get these insights into molecular-level interactions due to the technology at ImPaKT,” said Heinrichs, whose lab focuses on MRSA and finding drugs to treat MRSA infections. “The next step would be to replicate this study in relevant animal models.”

    Source:

    University of Western Ontario

    Journal reference:

    Goncheva, M. I., et al. (2023). The Staphylococcus aureus protein IsdA increases SARS CoV-2 replication by modulating JAK-STAT signaling. IScience. doi.org/10.1016/j.isci.2023.105975.

    Microbiology

    Vaginal sex can shape the composition of urethral microbiome in healthy men

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    Reviewed by Emily Henderson, B.Sc.Mar 21 2023

    Contrary to common beliefs, your urine is not germ free. In fact, a new study shows that the urethra of healthy men is teeming with microbial life and that a specific activity-;vaginal sex-;can shape its composition. The research, published March 24 in the journal Cell Reports Medicine, provides a healthy baseline for clinicians and scientists to contrast between healthy and diseased states of the urethra, an entrance to the urinary and reproductive systems.

    We know where bugs in the gut come from; they primarily come from our surroundings through fecal-oral transfer. But where does genital microbiology come from?”

    David Nelson, co-senior author, microbiologist at Indiana University

    To flush out the answer, the team of microbiologists, statisticians, and physicians sequenced the penile urethra swabs of 110 healthy adult men. These participants had no urethral symptoms or sexually transmitted infections (STIs) and no inflammation of the urethra. DNA sequencing results revealed that two types of bacterial communities call the penile urethra home-;one native to the organ, the other from a foreign source.

    “It is important to set this baseline,” says co-senior author Qunfeng Dong, a bioinformatician at Loyola University Chicago. “Only by understanding what health is can we define what diseases are.”

    The researchers found that most of the healthy men had a simple, sparse community of oxygen-loving bacteria in the urethra. In addition, these bacteria probably live close to the urethral opening at the tip of the penis, where there is ample oxygen. The consistent findings of these bacteria suggest that they are the core community that supports penile urethra health.

    But some of the men also had a more complex secondary group of bacteria that are often found in the vagina and can disturb the healthy bacterial ecosystem of the vagina. The team speculates that these bacteria reside deeper in the penile urethra because they thrive in oxygen-scarce settings. Only men who reported having vaginal sex carry these bacteria, hinting at the microbes’ origins.

    Delving into the participant’s sexual history, the team found a close link between this second bacterial community and vaginal sex but not other sexual behaviors, such as oral sex and anal sex. They also found evidence that vaginal sex has lasting effects. Vagina-associated bacteria remained detectable in the participants for at least two months after vaginal sex, indicating that sexual exposure to the vagina can reshape the male urinary-tract microbiome.

    “In our study, one behavior explains 10% of the overall bacterial variation,” says Nelson, when discussing the influence of vaginal sex. “The fact that a specific behavior is such a strong determinant is just profound.”

    Although current findings from the study show that vaginal bacteria can spread to the penile urethra, the team’s next plan is to test whether the reverse is true. Using the newly established baseline, the researchers also hope to offer new insights into bacteria’s role in urinary- and reproductive-tract diseases, including unexplained urethral inflammation and STIs.

    “STIs really impact people who are socioeconomically disadvantaged; they disproportionately impact women and minorities,” says Nelson. “It’s a part of health care that’s overlooked because of stigma. I think our study has a potential to dramatically change how we handle STI diagnosis and management in a positive way.”

    This work was supported by the National Institute of Allergy and Infectious Diseases.

    Source:

    Cell Press

    Journal reference:

    Toh, E., et al. (2023). Sexual behavior shapes male genitourinary microbiome composition. Cell Reports Medicine. doi.org/10.1016/j.xcrm.2023.100981

    Microbiology

    “Glow-in-the-Dark” Proteins: The Future of Viral Disease Detection?

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    Although there have been significant advancements in diagnostic tests for viral diseases, many highly sensitive tests still rely on complex sample preparation and result interpretation methods, rendering them unsuitable for point-of-care settings or resource-limited areas. However, researchers have now revealed in ACS Central Science a novel, sensitive technique that can analyze viral nucleic acids in just 20 minutes using a one-step process with “glow-in-the-dark” proteins.

    Bioluminescence, the scientific phenomenon behind the firefly’s glow, the anglerfish’s radiant lure, and the ghostly blue of phytoplankton-laden shores, is powered by a chemical reaction involving the luciferase protein. This luminescent protein has been integrated into sensors that emit visible light when detecting their target, making them ideal for straightforward point-of-care testing. However, until now, these sensors have not achieved the exceptional sensitivity necessary for clinical diagnostic tests.

    The gene-editing technique known as CRISPR could provide this ability, but it requires many steps and additional specialized equipment to detect what can be a low signal in a complex, noisy sample. So, Maarten Merkx and colleagues wanted to use CRISPR-related proteins, but combine them with a bioluminescence technique whose signal could be detected with just a digital camera.

    To make sure there was enough sample RNA or DNA to analyze, the researchers performed recombinase polymerase amplification (RPA), a simple method that works at a constant temperature of about 100 F. With the new technique, called LUNAS (luminescent nucleic acid sensor), two CRISPR/Cas9 proteins specific for different neighboring parts of a viral genome each have a distinct fragment of luciferase attached to them.

    If a specific viral genome that the researchers were testing for was present, the two CRISPR/Cas9 proteins would bind to the targeted nucleic acid sequences and come close to each other, allowing the complete luciferase protein to form and shine blue light in the presence of a chemical substrate. To account for this substrate being used up, the researchers used a control reaction that shined green. A tube that changed from green to blue indicated a positive result.

    When tested on clinical samples collected from nasal swabs, RPA-LUNAS successfully detected SARS-CoV-2 RNA within 20 minutes, even at concentrations as low as 200 copies per microliter. The researchers say that the LUNAS assay has great potential for detecting many other viruses effectively and easily.

    Reference: “Glow-in-the-Dark Infectious Disease Diagnostics Using CRISPR-Cas9-Based Split Luciferase Complementation” by Harmen J. van der Veer, Eva A. van Aalen, Claire M. S. Michielsen, Eva T. L. Hanckmann, Jeroen Deckers, Marcel M. G. J. van Borren, Jacky Flipse, Anne J. M. Loonen, Joost P. H. Schoeber and Maarten Merkx, 15 March 2023, ACS Central Science.
    DOI: 10.1021/acscentsci.2c01467

    The study was funded by the Dutch Research Council | Nationaal Regieorgaan Praktijkgericht Onderzoek SIA (NRPO-SIA) and the Eindhoven University Fund.

    American Chemical Society

    Microbiology

    New, Better Models Show How Infectious Diseases Like COVID-19 Spread

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    The COVID-19 pandemic has emphasized the significance of modeling in comprehending the spread of diseases and in providing crucial insights into disease prevention and control. A new model has utilized COVID-19 data and combined two classic methodologies to enhance predictions about disease spread.

    A widely used modeling technique involves dividing the population into compartments, such as susceptible (S), infected (I), and recovered (R), in what is known as the SIR model. This approach models the rates of change that describe the movement of individuals from one compartment to another.

    KAUST researchers, led by Paula Moraga, integrated SIR compartment modeling in time and a point process modeling approach in space–time, while also taking into account age-specific contact patterns. To do this, they used a two-step framework that allowed them to model data on infectious locations over time for different age groups.

    “The model gives more accurate predictions than previous approaches when making short/mid-range predictions in space and time,” says lead researcher André Amaral.

    “It also accounts for different age classes so we can treat these groups separately, resulting in finer control over the number of infectious cases.”

    Their approach paid off. In a simulation study to assess the model’s performance, and in a case study of COVID-19 cases in Cali, Colombia, the model performed better when making predictions and provided similar results for past time points, compared with models commonly used in predictive modeling.

    “The model’s features can help decision-makers to identify high-risk locations and vulnerable populations to develop better strategies for disease control,” says Amaral.

    It also can be used with any infectious disease that fits the compartment model assumptions, such as influenza. Furthermore, the model can account for different age groups and their associated contact patterns, meaning it allows more detailed conclusions about where, when, and to which population group decision-makers should focus their resources if they want to control disease spread.

    “In future work, we might extend such an approach and use different temporal models to replace the SIR model. This would allow us to account for different epidemic dynamics and expand the number of scenarios that the model can be used for,” says Amaral.

    “Finally, to improve the model’s predictive capabilities, we might work on developing ensemble approaches that combine a number of predictions from a number of different models and also account for potential time delays in collecting data,” he adds.

    Moraga says the model’s performance demonstrates the importance of quality and detailed data by location, time, and population group to understand infectious disease dynamics while highlighting the need to strengthen national surveillance systems to improve public health decision-making.

    Reference: “Spatio-temporal modeling of infectious diseases by integrating compartment and point process models” by André Victor Ribeiro Amaral, Jonatan A. González and Paula Moraga, 13 December 2022, Stochastic Environmental Research and Risk Assessment.
    DOI: 10.1007/s00477-022-02354-4

    King Abdullah University of Science & Technology (KAUST)

    Microbiology

    Unexplained Digestive Problems? Lone Star Tick Bites May Be To Blame

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    The American Gastroenterological Association (AGA) has released new clinical guidance to help physicians and patients identify if unexplained digestive symptoms are due to alpha-gal syndrome, a food allergy that is caused by lone star tick bites. The AGA Clinical Practice Update was published today (March 21, 2023) in the medical journal Gastroenterology.

    Alpha-gal syndrome is an allergy that causes your body to react to eating meat from mammals and products made from mammals. Symptoms usually start 2-6 hours after eating the mammalian meat or food.

    Clinicians should consider alpha-gal syndrome in patients with unexplained gastrointestinal symptoms of abdominal pain, diarrhea, nausea, and vomiting, particularly those who live or have lived in an alpha-gal–prevalent area (this includes the Southeast, mid-Atlantic, Midwest, and East Central U.S. regions). For patients with suspected alpha-gal, there is a blood test that looks for immunoglobulin E antibodies (IgE) to alpha-gal. Patients with these antibodies may have alpha-gal allergy. The main treatment for alpha-gal allergy is to not eat foods that contain alpha-gal. This includes mammalian meat, fat, and products made from them.

    About Alpha-gal syndrome

    Alpha-gal syndrome is an allergy that causes your body to respond badly to ingesting mammalian products; meat from mammals or products made from mammals such as cheese, butter, milk, cream, gelatin, etc. Mammals are animals that have hair, such as cows, pigs, and deer.  Symptoms usually start 2-6 hours after eating the mammalian meat or food. The alpha-gal allergy can cause symptoms of the gastrointestinal tract (digestive system) like stomach pain, diarrhea (loose stool), nausea or upset belly, and vomiting (throwing up). It can also cause hives (an itchy rash), flushing of the skin, swelling of the face, or fainting.

    About lone star ticks

    Lone star ticks (Amblyomma americanum) are a species of tick found predominantly in the southeastern and eastern United States. They are named for the distinctive white spot on the back of adult females, which resembles the shape of the state of Texas. Lone star ticks are known for their aggressive behavior, feeding on a variety of hosts, including humans, dogs, and deer. They are also known to carry diseases such as Rocky Mountain spotted fever, tularemia, and alpha-gal syndrome, a food allergy that causes the body to react to mammalian meat.

    As the official journal of the AGA Institute, Gastroenterology is the leading publication in the field of gastrointestinal disease. It provides reliable and current coverage of both clinical and basic gastroenterology, with regular contributions from renowned experts and the latest information on disease treatments. Original research is categorized by clinical and basic-translational content, as well as by content related to the alimentary tract, liver, pancreas, and biliary system.

    American Gastroenterological Association

    Microbiology

    Emergence of extensively drug-resistant Shigella sonnei strain in France

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    Shigellosis, a highly contagious diarrheal disease, is caused by Shigella bacteria circulating in industrializing countries but also in industrialized countries. Scientists from the French National Reference Center for Escherichia coli, Shigella and Salmonella at the Institut Pasteur who have been monitoring Shigella in France for several years have detected the emergence of extensively drug-resistant (XDR) strains of Shigella sonnei. Bacterial genome sequencing and case characteristics (with most cases being reported in male adults) suggest that these strains, which originated in South Asia, mainly spread among men who have sex with men (MSM). This observation needs to be taken into account by clinicians and laboratories when testing for sexually transmitted infections (STIs) in MSM, and systematic antibiograms should be performed if a Shigella strain is isolated to improve treatment for patients infected with XDR strains. The results were published in the journal Nature Communications on January 26, 2023.

    Shigellosis is a highly contagious diarrheal disease that spreads through fecal-oral transmission. Among the different types of Shigella, Shigella sonnei is the species that mainly circulates in industrialized countries. Shigella sonnei infections can cause short-term diarrhea (3-4 days) that resolves on its own. Antibiotic treatment is, however, necessary for moderate to severe cases (bloody diarrhea, risk of complications) or to prevent person-to-person transmission in epidemic situations. The acquisition of antibiotic resistance mechanisms by Shigella bacteria therefore restricts therapeutic options.

    In this study, scientists from the National Reference Center for Escherichia coli, Shigella and Salmonella (CNR-ESS) at the Institut Pasteur demonstrate an increase in antibiotic resistance in S. sonnei isolates collected in France over the past 17 years. The study is based on an analysis of more than 7,000 S. sonnei isolates and epidemiological information gathered in connection with national shigellosis surveillance conducted by the CNR-ESS between 2005 and 2021. The CNR-ESS analyzes all the bacterial isolates sent by its network of private and public partner laboratories throughout France. Over this period, isolates described as “extensively drug resistant” (XDR) were identified for the first time in 2015. The scientists then observed that the proportion of XDR isolates, which are resistant to virtually all the antibiotics recommended for treating shigellosis, increased significantly and reached a peak in 2021, when 22.3% of all S. sonnei isolates (99 cases) were XDR.

    Genome sequencing revealed that all these French XDR strains belonged to the same evolutionary lineage, which became resistant to a key antibiotic (ciprofloxacin) in around 2007 in South Asia. In several geographical regions of the world, including France, the strains then acquired different plasmids coding for resistance to other first-line antibiotics (especially third-generation cephalosporins and azithromycin). For severe cases, the only antibiotics that are still effective are carbapenems or colistin, which must be administered intravenously, resulting in more aggressive treatment that requires more complex monitoring in a hospital environment.

    XDR isolates were observed in France in various contexts: in travelers returning from South Asia or South-East Asia, during an outbreak at a school in 2017 (more than 90 cases, leading to school closure; the index case had returned from South-East Asia) and in men who have sex with men (MSM). The latter were infected by an epidemic clone that has been spreading throughout Europe since 2020 but has also been found in North America and Australia. This subgroup of XDR strains circulating in MSM was the most widespread, accounting for 97% of XDR strains in France in 2021.

    Frequent use of antibiotics in South and South-East Asia, together with repeat treatment for STIs in some people potentially exposed to this risk, increase the likelihood of selection of XDR Shigella strains. Further research is needed to understand the different clinical forms of infection, and especially whether there are asymptomatic forms that might cause the bacteria to spread more widely. Therapeutic trials are also crucial to identify effective oral antibiotics for treating these XDR Shigella strains.

  • Sophie Lefèvre, Elisabeth Njamkepo, Sarah Feldman, Corinne Ruckly, Isabelle Carle, Monique Lejay-Collin, Laëtitia Fabre, Iman Yassine, Lise Frézal, Maria Pardos de la Gandara, Arnaud Fontanet, François-Xavier Weill. Rapid emergence of extensively drug-resistant Shigella sonnei in France. Nature Communications, 2023; 14 (1) DOI: 10.1038/s41467-023-36222-8

    • Institut Pasteur
    Microbiology

    CDC Warns of Deadly Fungus Spreading at Alarming Rate in U.S. Healthcare Facilities

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    Candida auris (C. auris), an emerging fungus considered an urgent antimicrobial resistance (AR) threat, spread at an alarming rate in U.S. healthcare facilities in 2020-2021, according to data from the Centers for Disease Control and Prevention (CDC) published in the Annals of Internal Medicine. Equally concerning was a tripling in 2021 of the number of cases that were resistant to echinocandins, the antifungal medicine most recommended for treatment of C. auris infections. In general, C. auris is not a threat to healthy people. People who are very sick, have invasive medical devices, or have long or frequent stays in healthcare facilities are at increased risk for acquiring C. auris. CDC has deemed C. auris as an urgent AR threat, because it is often resistant to multiple antifungal drugs, spreads easily in healthcare facilities, and can cause severe infections with high death rates.

    “The rapid rise and geographic spread of cases is concerning and emphasizes the need for continued surveillance, expanded lab capacity, quicker diagnostic tests, and adherence to proven infection prevention and control,” said CDC epidemiologist Dr. Meghan Lyman, lead author of the paper.

    As further explained in the article, C. auris has spread in the United States since it was first reported in 2016, with a total of 3,270 clinical cases (in which infection is present) and 7,413 screening cases (in which the fungus is detected but not causing infection) reported through December 31, 2021. Clinical cases have increased each year since 2016, with the most rapid rise occurring during 2020-2021. CDC has continued to see an increase in case counts for 2022. During 2019-2021, 17 states identified their first C. auris case ever. Nationwide, clinical cases rose from 476 in 2019 to 1,471 in 2021. Screening cases tripled from 2020 to 2021, for a total of 4,041. Screening is important to prevent spread by identifying patients carrying the fungus so that infection prevention controls can be used.

    C. auris case counts have increased for many reasons, including poor general infection prevention and control (IPC) practices in healthcare facilities. Case counts may also have increased because of enhanced efforts to detect cases, including increased colonization screening, a test to see if someone has the fungus somewhere on their body but does not have an infection or symptoms of infection. The timing of this increase and findings from public health investigations suggest C. auris spread may have worsened due to strain on healthcare and public health systems during the COVID-19 pandemic.

    The CDC’s Antimicrobial Resistance Laboratory Network, which provides nationwide lab capacity to rapidly detect antimicrobial resistance and inform local responses to prevent spread and protect people, provided some of the data for this report. CDC worked to significantly strengthen laboratory capacity, including in state, territorial, and local health departments, through supplemental funding supported by the American Rescue Plan Act. These efforts include increasing susceptibility testing capacity for C. auris from seven Regional Labs to more than 26 labs nationwide.

    CDC continues to work with state, local, and territorial health departments and other partners to address this emerging threat to public health. Review more information on C. auris, the Antimicrobial Resistance Threats Report that identified C. auris as an urgent threat in the United States, or the WHO fungal priority pathogen list that identifies C. auris as a priority globally.

    Reference: “Worsening Spread of Candida auris in the United States, 2019 to 2021” by Meghan Lyman, MD, Kaitlin Forsberg, MPH, D. Joseph Sexton, PhD, Nancy A. Chow, PhD, MS, Shawn R. Lockhart, PhD, Brendan R. Jackson, MD, MPH and Tom Chiller, MD, MPHTM, 21 March 2023, Annals of Internal Medicine.
    DOI: 10.7326/M22-3469

    Centers for Disease Control and Prevention

    Microbiology

    Leaving lymph nodes intact until after immunotherapy could boost efficacy against solid tumors

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    Reviewed by Emily Henderson, B.Sc.Mar 20 2023

    Cancer treatment routinely involves taking out lymph nodes near the tumor in case they contain metastatic cancer cells. But new findings from a clinical trial by researchers at UC San Francisco and Gladstone Institutes shows that immunotherapy can activate tumor-fighting T cells in nearby lymph nodes.

    The study, published March 16, 2023 in Cell, suggests that leaving lymph nodes intact until after immunotherapy could boost efficacy against solid tumors, only a small fraction of which currently respond to these newer types of treatments.

    Most immunotherapies are aimed only at reinvigorating T cells in the tumor, where they often become exhausted battling the tumor’s cancer cells. But the new research shows that allowing the treatment to activate the immune response of the lymph nodes as well can play an important role in driving positive response to immunotherapy.

    This work really changes our thinking about the importance of keeping lymph nodes in the body during treatment.”

    Matt Spitzer, PhD, investigator for the Parker Institute for Cancer Immunotherapy and Gladstone-UCSF Institute of Genomic Immunology and senior author of the study

    Lymph nodes are often removed because they are typically the first place metastatic cancer cells appear, and without surgery, it can be difficult to determine whether the nodes contain metastases.

    “Immunotherapy is designed to jump start the immune response, but when we take out nearby lymph nodes before treatment, we’re essentially removing the key locations where T cells live and can be activated,” Spitzer said, noting that the evidence supporting the removal of lymph nodes is from older studies that predate the use of today’s immunotherapies.

    Aim for the lymph nodes, not the tumor

    Researchers have largely been working under the assumption that cancer immunotherapy works by stimulating the immune cells within the tumor, Spitzer said. But in a 2017 study in mice, Spitzer showed that immunotherapy drugs are actually activating the lymph nodes.

    “That study changed our understanding of how these therapies might be working,” said Spitzer. Rather than the immunotherapy pumping up the T cells in the tumor, he said, T cells in the lymph nodes are likely the source for T cells circulating in the blood. Such circulating cells can then go into the tumor and kill off the cancer cells.

    Having shown that intact lymph nodes can temper cancer’s hold in mice, Spitzer’s team wanted to know whether the same would prove true in human patients. They chose to design a trial for patients with head and neck cancers because of the high number of lymph nodes in those areas.

    The trial enrolled 12 patients whose tumors hadn’t yet metastasized past the lymph nodes. Typically, such patients would undergo surgery to remove the tumor, followed by other treatments if recommended.

    Instead, patients received a single cycle of an immunotherapy drug called atezolizumab (anti-PD-L1) that is produced by Genentech, a sponsor of the trial. A week or two later, Spitzer’s team measured how much the treatment activated the patients’ immune systems.

    The treatment also included surgically removing each patient’s tumor and nearby lymph nodes after immunotherapy and analyzing how the immunotherapy affected them.

    The team found that, after immunotherapy, the cancer-killing T cells in the lymph nodes began springing into action. They also found higher numbers of related immune cells in the patients’ blood.

    Spitzer attributes some of the trial’s success to its design, which allowed the team to get a lot of information from a small number of patients by looking at the tissue before and after surgery and running detailed analyses.

    “Being able to collect the tissue from surgery shortly after the patients had been given the drug was a really unique opportunity,” he said. “We were able to see, at the cellular level, what the drug was doing to the immune response.”

    That kind of insight would be challenging to get from a more traditional trial in patients with later-stage disease, who would not typically benefit from undergoing surgery after immunotherapy.

    Metastases inhibit immune response

    Another benefit of the study design was that it allowed researchers to compare how the treatment affected lymph nodes with and without metastases, or a second cancer growth.

    “No one had looked at metastatic lymph nodes in this way before,” said Spitzer. “We could see that the metastases impaired the immune response relative to what we saw in the healthy lymph nodes.”

    It could be that the T cells in these metastatic nodes were less activated by the therapy, Spitzer said. If so, that could explain, in part, the poor performance of some immunotherapy treatments.

    Still, the therapy prompted enough T-cell activity in the metastatic lymph nodes to consider leaving them in for a short period of time until treatment ends. “Removing lymph nodes with metastatic cancer cells is probably still important but taking them out before immunotherapy treatment may be throwing the baby out with the bathwater,” said Spitzer.

    A subsequent goal of the current trial is to determine whether giving immunotherapy before surgery protects against the recurrence of tumors in the future. Researchers won’t know the answer to that until they’ve had a chance to monitor the participants for several years.

    “My hope is that if we can activate a good immune response before the tumor is taken out, all those T cells will stay in the body and recognize cancer cells if they come back,” Spitzer said.

    Next, the team plans to study better treatments for patients with metastatic lymph nodes, using drugs that would be more effective at reactivating their immune responses.

    Source:

    University of California – San Francisco

    Journal reference:

    Rahim, M. K., et al. (2023). Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell. doi.org/10.1016/j.cell.2023.02.021