Tag Archives: Allergy

Microbiology

University of Louisville researchers receive $5.8 million to prevent immune system dysregulation

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Reviewed by Megan Craig, M.Sc.Jun 2 2023

Researchers at the University of Louisville have received $5.8 million in two grants from the National Institutes of Health to expand their work to better understand and prevent immune system dysregulation responsible for acute respiratory distress, the condition responsible for serious illness and death in some COVID-19 patients. A separate $306,000 NIH Small Business Innovation Research grant supports early testing of a compound developed at UofL as a potential treatment.

The three grants combined total $6.1 million.

During the pandemic, health care providers worked tirelessly to treat patients who became seriously ill with COVID-19. Some of those patients developed severe lung disease known as acute respiratory distress syndrome (ARDS) due to an excessive response of the immune system often called cytokine storm.

As they treated these critically ill patients, physicians and other providers at UofL Health shared their clinical insights and patient samples with researchers at UofL to discover the cause of the immune system overresponse.

At one time we had over 100 patients with COVID in the hospital. Once they were on a ventilator, mortality was about 50%. We were looking at this issue to see why some people would do well while some developed bad lung disease and did not do well or died.”

Jiapeng Huang, an anesthesiologist with UofL Health and professor and vice chair of the Department of Anesthesiology and Perioperative Medicine in the UofL School of Medicine

The UofL researchers, led by immunologist Jun Yan, discovered that a specific type of immune cells, low-density inflammatory neutrophils, became highly elevated in some COVID-19 patients whose condition became very severe. This elevation signaled a clinical crisis point and increased likelihood of death within a few days due to lung inflammation, blood clotting and stroke. Their findings were published in 2021 in JCI Insight.

With the new NIH funding, Yan is leading research to build on this discovery with deeper understanding of what causes a patient’s immune system to respond to an infection in this way and develop methods to predict, prevent or control the response.

“Through this fruitful collaboration, we now have acquired NIH funding for basic and translational studies and even progress toward commercialization of a potential therapy,” Yan said. “That’s why we do this research – eventually we want to benefit the patients.”

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Yan, chief of the UofL Division of Immunotherapy in the Department of Surgery, a professor of microbiology and immunology and a senior member of the Brown Cancer Center, will lead the new research, along with Huang and Silvia M. Uriarte, university scholar and professor in the Department of Oral Immunology and Infectious Diseases in the UofL School of Dentistry.

“COVID-19 continues to spotlight the impactful synergy between the clinical and research teams at the University of Louisville,” said Jason Smith, UofL Health chief medical officer. “Innovation is in the DNA of academic medicine. We collaborate to provide each patient the best options for prevention and treatment today, while developing the even better options for tomorrow.”

In addition to two research grants of $2.9 million each awarded directly to UofL, a $306,000 grant to a startup company will support early testing of a compound developed in the lab of UofL Professor of Medicine Kenneth McLeish that shows promise in preventing the dangerous cytokine storm while allowing the neutrophils to retain their ability to kill harmful bacteria and viruses. The compound, DGN-23, will be tested by UofL and Degranin Therapeutics, a startup operated by McLeish, Yan, Huang, Uriarte and Madhavi Rane, associate professor in the Department of Medicine.

“This is one more example of how UofL has led the charge in finding new and innovative ways to detect, contain and fight COVID-19 and other potential public health threats,” said Kevin Gardner, UofL’s executive vice president for research and innovation. “This team’s new research and technology could help keep people healthy and safe here and beyond.”

The knowledge gained through these studies may benefit not only COVID-19 patients, but those with other conditions in which immune dysregulation can occur, such as other types of viral and bacterial pneumonia and autoimmune diseases, and patients undergoing cancer immunotherapy and organ transplantation.

The grants

Grant 1 – $2.9 million, four-year grant to UofL. Investigators will study the new subset of neutrophils Yan identified to better understand how they contribute to acute respiratory distress and clotting. They also will determine whether a novel compound will prevent these complications. They will use lab techniques and studies with animal models that allow for manipulation of certain conditions that cannot be done in human subjects.

Grant 2 – $2.9 million, five-year grant to UofL. This work examines a more comprehensive landscape to characterize different subsets of neutrophils and measure their changes over the course of COVID-19 disease progression and how neutrophils contribute to immune dysfunction.

Grant 3 – $306,000, one-year grant to Degranin Therapeutics and UofL for early testing of DGN-23, a compound developed at UofL, to determine its effectiveness in preventing or reducing immune dysregulation.

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Source:

University of Louisville

Microbiology

First-in-human nanoparticle HIV vaccine induces broad and publicly targeted helper T cell responses

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Reviewed by Lily Ramsey, LLMMay 25 2023

Researchers from Fred Hutchinson Cancer Center in Seattle, Scripps Research in La Jolla, California, IAVI and other collaborating institutions have characterized robust T-cell responses in volunteers participating in the IAVI G001 Phase 1 clinical trial to test the safety and immune response of a self-assembling nanoparticle HIV vaccine.

Their work, published in Science Translational Medicine, signals a major step toward development of a vaccine approach to end the HIV/AIDS epidemic worldwide. The antigen used in this study was jointly developed by IAVI and Scripps Research and has been shown in previous analyses to stimulate VRC01-class B cells, an immune response considered promising enough for boosting in further studies.

We were quite impressed that this vaccine candidate produced such a vigorous T-cell response in almost all trial participants who received the vaccine. These results highlight the potential of this HIV-1 nanoparticle vaccine approach to induce the critical T-cell help needed for maturing antibodies toward the pathway of broadly neutralizing against HIV.”

Julie McElrath, MD, PhD, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division and co-senior author of the study

However, she added, this is the first step, and heterologous booster vaccines will still be needed to eventually produce VRC01-class broadly neutralizing antibodies, which in previous studies have demonstrated the ability to neutralize approximately 90% of HIV strains.

“We showed previously that this vaccine induced the desired B-cell responses from HIV broadly neutralizing antibody precursors. Here we demonstrated strong CD4 T-cell responses, and we went beyond what is normally done by drilling down to identify the T cell epitopes and found several broadly immunogenic epitopes that might be useful for developing boosters and for other vaccines,” William Schief, PhD, executive director of vaccine design for IAVI’s Neutralizing Antibody Center at Scripps Research and professor, Department of Immunology and Microbiology, at Scripps Research, who is co-senior author of the study.

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The trial is a phase 1, randomized, double-blind and placebo-controlled study to evaluate the safety and effectiveness of a nanoparticle HIV vaccine in healthy adult volunteers without HIV. It was comprised of two groups with 18 vaccine and six placebo recipients per group, with 48 total enrollees. Participants were given two doses of the vaccine or placebo eight weeks apart.

McElrath acknowledged the groundbreaking work of her lab team, the biostatistical team and Fred Hutch’s Vaccine Trials Unit for their invaluable contributions to the study. The Vaccine Trials Unit conducts multiple vaccine trials and was one of only two sites for this study.

Findings from the study include:

  • Vaccine-specific CD4 T cells were induced in almost all vaccine recipients.
  • Lymph node GC T follicular helper cells increased after vaccination compared to placebo.
  • Lumazine synthase protein, needed for self-assembly of the particle, also induced T-cell responses that can provide additional help to ultimately enhance efficacy in a sequential vaccine strategy.
  • Vaccine-specific CD4 T cells were polyfunctional and had diverse phenotypes.
  • LumSyn-specific CD8 T cells were highly polyfunctional and had a predominantly effector memory phenotype.
  • CD4 T-cell responses were driven by immunodominant epitopes with diverse and promiscuous HLA restriction.
  • CD8 T-cell responses to LumSyn were driven by HLA-A*02-restricted immunodominant epitopes B- and T-cell responses correlated within but not between LN and peripheral blood compartments.

This study was funded by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; IAVI Neutralizing Antibody Center; National Institute of Allergy and Infectious Diseases; and Ragon Institute of MGH, MIT and Harvard.

Study authors WRS and SM are inventors on a patent filed by Scripps and IAVI on the eOD-GT8 monomer and 60-mer immunogens (patent number 11248027, “Engineered outer domain (eOD) of HIV gp 120 and mutants thereof”). WRS, KWC and MJM are inventors on patents filed by Scripps, IAVI and Fred Hutch on immunodominant peptides from LumSyn (Title: Immunogenic compositions; filing no. 63127975).

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Source:

Fred Hutchinson Cancer Center

Journal reference:

Cohen, K. W., et al. (2023) A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Science Translational Medicine. doi.org/10.1126/scitranslmed.adf3309.

Microbiology

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

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Reviewed by Danielle Ellis, B.Sc.May 18 2023

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:

Washington University School of Medicine

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.

Microbiology

Discontinuing oral antibiotics after breast reconstruction does not lead to an increase in infections

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Reviewed by Emily Henderson, B.Sc.Apr 27 2023

For breast cancer patients undergoing breast reconstruction after mastectomy, avoiding postoperative oral antibiotics does not reduce the risk of infections, reports a study in the May issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS). The journal is published in the Lippincott portfolio by Wolters Kluwer.

Our experience suggests that discontinuing routine oral antibiotic treatment after implant-based breast reconstruction does not lead to an increase in surgical site infections, and will eliminate a small but significant risk of allergy and other antibiotic-related complications.”

Mark Sisco, MD, ASPS Member Surgeon, NorthShore University HealthSystem, Evanston, Ill

No increase in infections after policy change on preventive antibiotics

A growing number of breast cancer patients are undergoing breast reconstruction after mastectomy, particularly immediate reconstruction using implants. Surgical site infections (SSIs) occur in 10% to 25% of patients undergoing this procedure, leading to increased rates of hospital readmission, repeat surgery, and reconstructive failure.

Historically, plastic surgeons have given extended antibiotic prophylaxis (EAP) to reduce the risk of SSI. The use of postoperative oral antibiotics has continued despite a lack of evidence for its effectiveness, and amid rising concerns about antibiotic resistance. In 2016, the authors’ health system joined the growing trend toward ending routine EAP for post-mastectomy breast reconstruction.

To evaluate the impact of this practice change, Dr. Sisco and colleagues compared outcomes in two groups of patients: 654 women (1,004 breasts) receiving EAP and 423 women (683 breasts) not receiving postoperative oral antibiotics. Both groups received a single dose of intravenous antibiotic before surgery.

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After surgery, the overall infection rate was similar between groups: 7.9% with EAP and 9.1% without EAP. After adjustment for differences in patient characteristics, the risk of SSIs was not significantly different between groups. This was even though patients in the non-EAP were more likely to receive some newer techniques – including nipple-sparing mastectomy and pre-pectoral (“above the muscle”) implant placement – thought to carry an increased risk of complications.

‘Thousands of women nationwide’ may have adverse reactions to EAP

Meanwhile, patients receiving EAP had some “infrequent but not insignificant” adverse events, including a two percent rate of moderate to severe allergic reactions. At least four women in the EAP group developed infection with antibiotic-resistant Clostridium difficile (“C-diff”) bacteria. Neither of these complications occurred in patients who did not receive extended antibiotics.

There was also evidence that EAP affected the types of bacteria isolated from patients who developed infections, including a higher rate of gram-negative bacteria. Extended antibiotic use was associated with a “broader range of pathogens” and more frequent need for second-line intravenous antibiotics.

“Although the use of EAP does not appear to worsen clinical outcomes, marked differences in the microbiology of associated infections may make them more difficult to treat,” Dr. Sisco and coauthors write. Especially at a time when breast reconstruction rates are rapidly increasing, “Our findings suggest that thousands of women are having adverse reactions to EAP nationwide, and some of these are likely to be serious,” the researchers add.

While acknowledging some important limitations of their study, the authors note that a definitive randomized trial of ending routine EAP is unlikely to be performed. Dr. Sisco and colleagues conclude, “We hope that our experience will give surgeons additional evidence and courage to change their practice.”

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Source:

Wolters Kluwer

Journal reference:

Sisco, M., et al. (2022). Oral antibiotics do not prevent infection or implant loss after immediate prosthetic breast reconstruction: Evidence from 683 consecutive reconstructions without prophylaxis. Plastic & Reconstructive Surgery. doi.org/10.1097/prs.0000000000010073

Microbiology

Most kids recover from Lyme disease within six months of completing antibiotic treatment

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

A majority of parents of children diagnosed with Lyme disease reported that their kids recovered within six months of completing antibiotic treatment, according to a new joint study from Children’s National Research Institute and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, published in Pediatric Research. The findings, based on Lyme disease treatment outcome data from 102 children in the United States, also revealed that a notably small percentage of children took longer than six months to recover and experienced a significant impact on their daily functioning.

Lyme disease is the most common vector-borne disease in the United States, with most cases caused by the bacterium Borrelia burgdorferi transmitted through the bites of infected blacklegged or deer ticks. Children between the ages 5 and 9 years account for a large proportion of the approximately 476,000 Lyme disease cases diagnosed and treated annually in the United States. Common symptoms of Lyme disease include: fever; headache; fatigue; and a distinct skin rash called erythema migrans. Without treatment, the infection can spread to joints, the heart and the nervous system. Antibiotic treatment resulting in full recovery is successful in most Lyme cases. For some, however, symptoms of pain, fatigue, or difficulty thinking persist or return after antibiotic treatment. Symptoms that substantially reduce levels of activity and impact quality of life for more than six months after treatment are classified as post-treatment Lyme disease (PTLD) syndrome.

This research studied the long-term outcomes of children with Lyme disease through a cross-sectional evaluation using validated surveys. The study collected survey responses from the parents of 102 children ages 5 to 18 years who had been diagnosed with Lyme disease between six months and 10 years before enrollment. Adolescents ages 10 to 18 years old were also invited to complete adolescent-specific questionnaires. According to these parent survey responses, 75% of children fully recovered within six months of completing treatment: 31% of all children recovered within one month; 30% recovered in one-to-three months; and 14% recovered in four-to-six months. Approximately 22% of children in the study experienced at least one symptom that persisted six or more months after completing treatment; of those, 9% had symptoms classified as PTLD syndrome. Six percent of the children were not fully recovered at the time of the survey, with 1% experiencing symptoms significant enough to impair daily functioning, the authors noted.

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According to the authors, this study supports previous data showing an excellent overall prognosis for children with Lyme disease, which should help alleviate understandable parental stress associated with lingering non-specific symptoms among infected children. They note that the findings of this study can help clinicians manage families’ expectations about the varying post-treatment recovery times of pediatric Lyme disease patients. The researchers suggest this new data could help reduce the potential for families seeking dangerous alternative therapies for children who experience prolonged recovery times. PTLD syndrome remains poorly understood in children and adults, and more research is needed to better understand these prolonged symptoms and identify treatment targets, according to the authors.

This study was supported through a partnership between NIAID and the Children’s National Research Institute (CNRI). Researchers at the Center for Translational Research at CNRI and the NIAID Laboratory of Clinical Immunology and Microbiology conducted the study.

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Source:

NIH/National Institute of Allergy and Infectious Diseases

Journal reference:

Monaghan, M., et al. (2023). Pediatric Lyme disease: systematic assessment of post-treatment symptoms and quality of life. Pediatric Research. doi.org/10.1038/s41390-023-02577-3.

Microbiology

GW one of 18 clinical trial sites across the United States testing monkeypox vaccine in adolescents

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Reviewed by Emily Henderson, B.Sc.Apr 19 2023

The National Institutes of Health trial to evaluate the mpox (previously known as monkeypox) vaccine JYNNEOS has now entered the next stage and is studying the immune responses to and the safety of the vaccine in adolescents. The George Washington University is one of 18 clinical trial sites across the United States that have launched this stage testing the JYNNEOS vaccine.

The JYNNEOS vaccine was approved by the U.S. Food and Drug Administration for use in adults in 2019 and, in 2022, was authorized for use in people under 18 years of age on an emergency use basis. The latest stage of the trial, which is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, will look to see if the vaccine is safe and triggers an immune response in adolescents ages 12 to 17 that is comparable to adults ages 18 to 50 years. GW’s participation is funded through a contract with Frederick National Laboratory for Cancer Research, operated by Leidos Biomedical Research in Frederick, Maryland, which provides scientific support to NIH.

We are excited to have launched the next stage of this clinical trial, which can help determine if this vaccine can be used to protect adolescents should there be another large outbreak in the United States or some other part of the world.”

David Diemert, clinical director, George Washington University Vaccine Research Unit and professor of medicine, GW School of Medicine and Health Sciences

The GW Vaccine Research Unit is a collaboration between the Departments of Medicine and Microbiology, Immunology and Tropical Medicine located at the George Washington University School of Medicine and Health Sciences, and the GW Medical Faculty Associates. The GW Vaccine Research Unit conducts clinical trials of experimental products that are being developed for the prevention of infectious diseases.

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The clinical investigators at GW and the other sites plan to test 135 adults ages 18 to 50 who will serve as a comparison group in this stage of the study. The researchers will also recruit about 315 adolescents ages 12 to 17 years. All of the recruits will get the standard dose of the vaccine delivered subcutaneously, Diemert said.

The trial will last for 13 months and investigators will check for safety and to see if the antibody response in adolescents in the study are comparable to that of adults.

Mpox historically occurs in West and Central Africa, but in 2022, a large outbreak began in the United States and other countries around the world where mpox is uncommon. The virus spreads through close contact with an infected person or animal.

Although kids in the United States rarely get mpox, experts say children and teens can and do get this painful and sometimes deadly disease.

“Having a safe and effective vaccine at the ready would help prepare the United States and other countries for the next outbreak of this disease,” Diemert said.

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Source:

George Washington University

Microbiology

The importance and challenges of developing mucosal SARS-COV-2 vaccines

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Reviewed by Emily Henderson, B.Sc.Apr 13 2023

In November 2022, the National Institute of Allergy and Infectious Diseases (NIAID) co-hosted a virtual workshop on the importance and challenges of developing mucosal vaccines for SARS-COV-2. The highlights of this workshop have now been published as a report in npj Vaccines.

Although vaccines currently available for COVID-19 are usually effective at preventing severe disease, hospitalizations and death, researchers recognize the need for improvement. A vaccine more effective at preventing transmission or infection with SARS-CoV-2 could reduce overall replication of the virus and associated disease burden. Because SARS-CoV-2 enters the body and is transmitted via the respiratory tract, a vaccine to promote a mucosal immune response in the respiratory tract could be better at blocking transmission and infection. Although at least 44 mucosal vaccines are currently in preclinical development, and several more are in clinical development or authorized for use in other countries, no COVID-19 mucosal vaccines have been authorized for use by regulatory agencies in the United States or Europe.

NIAID partnered with the Coalition for Epidemic Preparedness Innovation, the Bill and Melinda Gates Foundation, the Biomedical Advanced Research and Development Authority, and the Wellcome Trust to develop the workshop. Over the course of the two-day event (November 7-8 2022), vaccine researchers and developers met virtually in eight sessions and discussed challenges and priorities in mucosal vaccine development.

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For instance, new correlates of protection must be identified and verified to evaluate whether a vaccine improves recipients’ mucosal immune responses to SARS-CoV-2, and to facilitate clinical testing and regulatory approval. Improved animal models are needed to help researchers develop potential mucosal vaccines, according to the report. Careful clinical design is needed to assess the unique safety concerns related to mucosal vaccines and to appropriately evaluate whether a vaccine can block transmission of the virus. Trial design also needs to account for how vaccines will be used. Since most people have either received a SARS-CoV-2 vaccine or had a natural infection, mucosal vaccines likely will be used as boosters, and researchers will need to know how well vaccines function in people who have some prior immunity. The means of delivery also must be considered: nasal sprays, pills, liquids taken by mouth, and even nebulizers could deliver a vaccine more directly to the respiratory system, but each of these poses unique challenges to manufacture, test and deliver.

Despite these and other challenges, attendees of the workshop were optimistic about the future of mucosal vaccines for COVID-19. Considering the potential benefits that a successful candidate could bring, they concluded that research needed to further mucosal vaccine development is a priority. Such research also could even lead to improved vaccines for other diseases, such as influenza, respiratory syncytial virus (RSV) or tuberculosis, in addition to advancing COVID-19 vaccinology.

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Source:

National Institute of Allergy and Infectious Diseases

Journal reference:

Knisely, J. M., et al. (2023). Mucosal vaccines for SARS-CoV-2: scientific gaps and opportunities—workshop report. Npj Vaccines. doi.org/10.1038/s41541-023-00654-6

Microbiology

Mosquitoes’ saliva contains immune-dampening substances to increase infectivity of dengue viruses

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Reviewed by Emily Henderson, B.Sc.Apr 4 2023

The saliva of mosquitoes infected with dengue viruses contains a substance that thwarts the human immune system and makes it easier for people to become infected with these potentially deadly viruses, new research reveals.

Dengue has spread in recent years to Europe and the Southern United States in addition to longstanding hotspots in tropical and subtropical areas such as Southeast Asia, Africa and Latin America. The new discovery, from a University of Virginia School of Medicine scientist and his collaborators, helps explain why the disease is so easily transmitted and could eventually lead to new ways to prevent infection.

“It is remarkable how clever these viruses are – they subvert mosquito biology to tamp down our immune responses so that infection can take hold,” said Mariano A. Garcia-Blanco, MD, PhD, who recently joined UVA as chair of the Department of Microbiology, Immunology and Cancer Biology. “There is no doubt in my mind that better understanding of the fundamental biology of transmission will eventually lead to effective transmission-blocking measures.”

Further, Garcia-Blanco suspects that researchers will find similar immune-dampening substances accompanying other mosquito-borne infections such as Zika, West Nile and yellow fever.

Our findings are almost certainly going to be applicable to infections with other flaviviruses. The specific molecules here are unlikely to apply to malaria, but the concept is generalizable to viral infections.”

Mariano A. Garcia-Blanco, MD, PhD, UVA

Understanding dengue

Approximately half the world’s population is at risk for dengue, and roughly 400 million people are infected every year. Dengue’s symptoms, including fever, nausea and skin rash, are often mistaken for other diseases. Most people will have mild cases, but about 1 in 20 will develop severe illness that can lead to shock, internal bleeding and death. Unfortunately, it’s possible to contract dengue repeatedly, as it is caused by four related viruses transmitted primarily by the Aedes aegypti species of mosquito. There is no treatment, but the new discovery from Garcia-Blanco and his colleagues identifies an important contributor to the disease’s spread as researchers seek to find better ways to combat it.

Garcia-Blanco and his team found that infected mosquitoes’ saliva contained not just the expected dengue virus but a powerful conspirator: molecules produced by the virus that can blunt the body’s immune response. The injection of these molecules, called sfRNAs, during the mosquito bite makes it more likely that the victim will become infected with dengue, the scientists conclude.

“By introducing this RNA at the biting site, dengue-infected saliva prepares the terrain for an efficient infection and gives the virus an advantage in the first battle between it and our immune defenses,” the researchers write in a new scientific paper outlining their findings.

Scientists who study mosquitoes previously had suspected that the insects’ saliva might contain some type of payload to enhance the potential for infection. Garcia-Blanco’s team’s new findings pinpoints one weapon in the viruses’ arsenal and opens the door to finding new ways to help reduce transmission and control the disease’s spread. For now, the best way to avoid getting seriously sick with dengue remains to avoid getting bitten.

“It’s incredible that the virus can hijack these molecules so that their co-delivery at the mosquito bite site gives it an advantage in establishing an infection,” said researcher Tania Strilets, a graduate student with Garcia-Blanco and co-first author of the scientific paper. “These findings provide new perspectives on how we can counteract dengue virus infections from the very first bite of the mosquito.”

Findings published

The researchers have published their findings in the scientific journal PLOS Pathogens. The team consisted of Shih-Chia Yeh, Strilets, Wei-Lian Tan, David Castillo, Hacène Medkour, Félix Rey-Cadilhac, Idalba M. Serrato-Pomar, Florian Rachenne, Avisha Chowdhury, Vanessa Chuo, Sasha R. Azar, Moirangthem Kiran Singh, Rodolphe Hamel, Dorothée Missé, R. Manjunatha Kini, Linda J. Kenney, Nikos Vasilakis, Marc A. Marti-Renom, Guy Nir, Julien Pompon and Garcia-Blanco. Most of Garcia-Blanco’s work on the project was conducted while he was at Duke-NUS Medical School and the University of Texas Medical Branch.

Source:

University of Virginia Health System

Journal reference:

Yeh, S.-C., et al. (2023). The anti-immune dengue subgenomic flaviviral RNA is present in vesicles in mosquito saliva and is associated with increased infectivity. PLOS Pathogens. doi.org/10.1371/journal.ppat.1011224.

Microbiology

Scientists identify a distinct role of retinoic acid during immune response of the gut

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Reviewed by Emily Henderson, B.Sc.Mar 28 2023

A team of scientists from the Renaissance School of Medicine (RSOM) at Stony Brook University have identified a distinct role of retinoic acid, a metabolite of vitamin A, during the immune response of the gut. This finding, detailed in a paper published in the Journal of Experimental Medicine, and highlighted in a broader piece in the journal, could help lead to ways to control the retinoic acid response and therefore be used as a therapy or for vaccine development against infection or even to treat GI tumors.

Led by Brian Sheridan, PhD, Associate Professor in the Department of Microbiology and Immunology and Center for Infectious Diseases, the study involves basic research that centers on unraveling the factors that control the generation of cytotoxic memory CD8 T cells, which are an important arm of the body’s anti-pathogen immune response as they kill pathogen-infected cells and produce anti-pathogen cytokines. In fact, memory CD8 T cells provide long-lived and frontline protection at barrier tissues, highlighting their importance in vaccine design.

To date scientists have known that retinoic acid in the gut-draining lymph nodes promotes effector CD8 T cell migration to the intestines, enhancing the immune response. Additionally, vitamin A deficiency is associated with increased infections and poor vaccine efficiency.

Sheridan and his co-authors, including Zhijuan Qiu, PhD, a post-doctoral fellow in the department, identified a new role for retinoic acid, which is a key part of the immune process in the gut. They demonstrated in the lab that T cell activation in gut-associated lymph nodes regulates memory CD8 T cell differentiation in the intestine. They also demonstrated in contrast that T cells activated at other sites were impaired in the ability to differentiate into memory CD8 T cells after entry into the intestine.

During this process, they demonstrated that activation within the gut-associated lymph nodes, but not in other sites, promotes intestinal memory CD8 T cell development and that retinoic acid signals provided during this window of T cell activation in the lymph nodes enhances intestinal memory CD8 T cell development to a wider degree.

Our study highlights a fundamental new role of T cell activation on the generation of the intestinal memory CD8 T cells that appears distinct from other barrier sites like the lungs and skin. Remarkably, we can alter intestinal T cell development by promoting or limiting retinoic acid signals during T cell activation, independent of the role of retinoic acid on T cell migration.”

Brian Sheridan, PhD, Associate Professor in the Department of Microbiology and Immunology and Center for Infectious Diseases

Because the research team was able to replicate this limiting or promoting of retinoic acid signals in the gut, they believe that manipulating retinoic acid signals during T cell activation may provide a strategy for clinicians to promote or limit intestinal CD8 T cells to improve vaccine outcomes or limit immunopathology.

This research is supported in part by a grant (R01AI172919) from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID) to Brian Sheridan.

Source:

Stony Brook University

Journal reference:

Qiu, Z., et al. (2023). Retinoic acid signaling during priming licenses intestinal CD103+ CD8 TRM cell differentiation. Journal of Experimental Medicine. doi.org/10.1084/jem.20210923.

Microbiology

NIH scientists discover an autoinflammatory disease caused by mutations in the LYN gene

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Reviewed by Emily Henderson, B.Sc.Mar 28 2023

Scientists have identified an autoinflammatory disease caused by mutations in the LYN gene, an important regulator of immune responses in health and disease. Named Lyn kinase-associated vasculopathy and liver fibrosis (LAVLI), the identification sheds light on how genes linked to certain illnesses can potentially be targets for treatment by repurposing existing drugs. The research, published in Nature Communications, was led by Adriana A. de Jesus, M.D. Ph.D., and Raphaela Goldbach-Mansky, M.D., M.H.S. of the Translational Autoinflammatory Diseases Section of the Laboratory of Clinical Immunology and Microbiology at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

LAVLI was first discovered in a pediatric patient through genetic testing, which detected a mutation in LYN, the gene that encodes the Lyn kinase protein. Two additional, unrelated pediatric patients were later discovered to have two more mutations in the same gene. All three patients developed diseases linked to the LYN genetic mutation shortly after birth. Two patients developed liver fibrosis—excessive amounts of scar tissue caused by inflammation and repeated liver damage—in the first year of life. All three patients had perinatal onset of neutrophilic cutaneous small vessel vasculitis. This is an immune disorder characterized by inflammation from high numbers of neutrophils—white blood cells of the immune system—that can damage small blood vessels.

The study revealed Lyn kinase was always active and unable to shut down in the three patients with the LYN mutation, which increased neutrophil migration, altered inflammatory signals and activated scar and fibrosis-inducing liver cells. The results of this study suggest that Lyn kinase may be a potential therapeutic target for drugs that treat forms of non-syndromic small vessel vasculitis and other types of inflammation-induced liver fibrosis.

Source:

National Institutes of Health

Journal reference:

de Jesus, A. A., et al. (2023). Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome. Nature Communications. doi.org/10.1038/s41467-023-36941-y.