Tag Archives: Medical research

New tool shows early promise to help reduce the spread of antimicrobial resistance

A new tool which could help reduce the spread of antimicrobial resistance is showing early promise, through exploiting a bacterial immune system as a gene editing tool.

Antimicrobial resistance is a major global threat, with nearly five million deaths annually resulting from antibiotics failing to treat infection, according to the World Health Organisation.

Bacteria often develop resistance when resistant genes are transported between hosts. One way that this occurs is via plasmids – circular strands of DNA, which can spread easily between bacteria, and swiftly replicate. This can occur in our bodies, and in environmental settings, such as waterways.

The Exeter team harnessed the CRISPR-Cas gene editing system, which can target specific sequences of DNA, and cuts through them when they are encountered. The researchers engineered a plasmid which can specifically target the resistance gene for Gentamicin – a commonly used antibiotic.

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In laboratory experiments, the new research, published in Microbiology, found that the plasmid protected its host cell from developing resistance. Furthermore, researchers found that the plasmid effectively targeted antimicrobial-resistant genes in hosts to which it transferred, reversing their resistance.

Antimicrobial resistance threatens to outstrip covid in terms of the number of global deaths. We urgently need new ways to stop resistance spreading between hosts. Our technology is showing early promise to eliminate resistance in a wide range of different bacteria. Our next step is to conduct experiments in more complex microbial communities. We hope one day it could be a way to reduce the spread of antimicrobial resistance in environments such as sewage treatment plants, which we know are breeding grounds for resistance.”

David Walker-Sünderhauf, Lead Author, University of Exeter

The research is supported by GW4, the Medical Research Council, the Lister Institute, and JPI-AMR.

Journal reference:

Walker-Sünderhauf, D., et al. (2023) Removal of AMR plasmids using a mobile, broad host-range, CRISPR-Cas9 delivery tool. Microbiology. doi.org/10.1099/mic.0.001334.

Study identifies key genetic mechanism of drug resistance in the deadliest malaria parasites

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An important genetic mechanism of drug resistance in one of the deadliest human malaria parasites has been identified in a new study published in Nature Microbiology.

A second key gene, pfaat1, responsible for encoding a protein that transports amino acids in the membrane of Plasmodium falciparum, is involved in its resistance to the major anti-malaria drug, chloroquine.

The findings may have implications for the ongoing battle against malaria, which infects an estimated 247 million people worldwide and kills more than 619,000 each year, most of which are young children.

Chloroquine is a major antimalaria drug, however in recent years, resistance has emerged in malaria parasites, first spreading through Southeast Asia and then through Africa in the 1970s and 1980s. Although alternative antimalarial drugs have been developed, resistance to chloroquine remains a big challenge.

Since its discovery in 2000, only one gene has been believed to have been responsible for resistance to chloroquine – the resistance transporter pfcrt which helps the malaria parasite transport the drug out of a key region in their cells, subsequently rendering it ineffective.

In this study, researchers from the Medical Research Council (MRC) Unit The Gambia at the London School of Hygiene & Tropical Medicine (LSHTM) analysed more than 600 genomes of P. falciparum that were collected in The Gambia over a period of 30 years. The team found that mutant variants of  a second gene, pfaat1, which encodes an amino acid transporter, increased in frequency from undetectable to very high levels between 1984 and 2014. Importantly, their genome-wide population analyses also indicated long term co-selection on this gene alongside the previously-known resistance gene pfcrt.

In the laboratory, a further team of researchers including from Texas Biomed, University of Notre Dame and Seattle Children’s Research Institute found that replacing these mutations in parasite genomes using CRISPR gene-editing technology impacted drug resistance. A team from Nottingham University also found that these mutations could impact the function of pfaat1 in yeast, resulting in drug resistance.

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Complementary analysis of malaria genome datasets additionally suggested that parasites from Africa and Asia may carry different mutations in pfaat1 which could help explain differences in the evolution of drug resistance across these continents.

Alfred Amambua-Ngwa, Professor of Genetic Epidemiology at MRC Unit The Gambia at LSHTM said: “This is a very clear example of natural selection in action – these mutations were preferred and passed on with extremely high frequency in a very short amount of time, suggesting they provide a significant survival advantage.

“The mutations in pfaat1 very closely mirror the increase of pfcrt mutations. This, and other genetic analyses in the paper demonstrate that the transporter AAT1 has a major role in chloroquine resistance.”

Grappling with drug resistance, for malaria and other pathogens, requires taking a holistic approach to both drug development and pathogen surveillance. We must be aware that different genes and molecules will be working together to survive treatments. That is why looking at whole genomes and whole populations is so critical.”

David Conway, Professor of Biology, LSHTM

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Journal reference:

Amambua-Ngwa, A., et al. (2023). Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1. Nature Microbiology. doi.org/10.1038/s41564-023-01377-z.

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

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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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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.

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

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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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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

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

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.

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.

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

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.

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.

Myeloid cells can harbor HIV in people taking antiretroviral therapy

A subset of white blood cells, known as myeloid cells, can harbor HIV in people who have been virally suppressed for years on antiretroviral therapy, according to findings from a small study supported by the National Institutes of Health. In the study, researchers used a new quantitative method to show that HIV in specific myeloid cells—short-lived monocytes and longer-lived monocyte-derived macrophages—can be reactivated and infect new cells. The findings, published in Nature Microbiology, suggest that myeloid cells contribute to a long-lived HIV reservoir, making these cells an important but overlooked target in efforts to eradicate HIV.

Our findings challenge the prevailing narrative that monocytes are too short-lived to be important in cure efforts. Yes, the cells are short-lived, but our follow-up data show that HIV can persist in monocytes over several years in people who are virally suppressed. The fact that we can detect HIV in these cells over such a long period suggests something is keeping the myeloid reservoir going.”

Rebecca Veenhuis, Ph.D., study author, assistant professor of molecular and comparative pathobiology and of neurology at Johns Hopkins University School of Medicine, Baltimore

The study, led by Veenhuis and colleagues at Johns Hopkins University School of Medicine, was supported by the National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, and the National Institute on Drug Abuse, all part of NIH.

Antiretroviral medications are effective in treating HIV because they prevent the virus from infecting new cells and multiplying. However, HIV may still exist in cells that are in a resting, or latent, state, creating an HIV reservoir. CD4 T cells, a type of white blood cell, are the most well-studied HIV reservoir. Identifying HIV reservoirs is critical to cure efforts, as latent HIV can be reactivated if people stop taking antiretroviral medications.

Monocytes are immune cells that circulate in the blood for about 3 days before traveling to tissue in various parts of the body, including the brain, where they can mature into macrophages. To date, it has not been clear whether latent HIV in these cells can become active again and infect other cells.

“What’s really important in the long run is understanding how monocytes contribute to the tissue macrophage reservoir,” explained Janice Clements, Ph.D., senior author on the study and professor of molecular and comparative pathobiology at Johns Hopkins University School of Medicine. “If monocytes can carry virus to the brain, or lung, or another part of the body and infect resident macrophages that are self-renewing and live almost indefinitely, that’s a real problem.”  

In the study, Veenhuis, Clements, and colleagues first measured HIV DNA in myeloid cells in a sample of 30 participants with HIV, all of whom were virally suppressed and had been on antiretroviral therapy for at least 5 years. They found detectable levels of HIV genetic material in monocytes and macrophages, though the levels were much lower than those observed in CD4 T cells. In some participants, the HIV genetic material found in monocytes was intact, which suggests it may be capable of infecting other cells if reactivated.

They then used the new quantitative method they developed to directly measure viral spread from HIV found in myeloid cells. The researchers isolated monocytes from blood samples taken from 10 participants and nurtured the monocytes in cultures that contained antiretroviral drugs, to replicate the participants’ baseline physical state. After the monocytes differentiated into macrophages, the researchers introduced an immune activating agent and then added fresh white bloods cells to allow for the virus to spread to new cells.

The researchers collected samples from the cell cultures several times over the next 12 days. They included checkpoints throughout the process to ensure that infected CD4 T cells did not interfere with their measurements.

The results showed that cultures from five of the 10 participants had detectable HIV genetic material in monocyte-derived macrophages that could be reactivated to infect other cells and produce more virus. The participants who had these reactivatable reservoirs of HIV in monocyte-derived macrophages had higher overall levels of HIV DNA material.  

Follow-up data from three participants showed that this reservoir can be long-lived, harboring latent HIV for months to several years. These reservoirs were stable and could be reactivated over time, indicating that monocyte-derived macrophages could contribute to viral rebound if antiretroviral treatment is disrupted.

The researchers note that this study is small and larger studies with more diverse participant pools will be essential to accurately estimate the proportion of people who have latent HIV in myeloid cells. Investigating the mechanisms that replenish the monocyte reservoir over time is a critical next step in this research.

“These findings underscore the importance of broadening the scope of HIV cure efforts,” said Joshua A. Gordon, M.D., Ph.D., director of the National Institute of Mental Health. “Shifting away from a sole focus on CD4 T cells to thinking about CD 4 T cells and myeloid cells together, in context, will propel the field toward more promising strategies for eradicating HIV.”

Journal reference:

Veenhuis, R. T., et al. (2023). Monocyte-derived macrophages contain persistent latent HIV reservoirs. Nature Microbiology. doi.org/10.1038/s41564-023-01349-3.

Study provides evidence for a strong role of autophagy in controlling intracellular infections

Researchers at the Francis Crick Institute have found that the body’s process of removing old and damaged cell parts, is also an essential part of tackling infections that take hold within our cells, like TB.

If this natural process can be harnessed with new treatments, it could present an alternative to, or improve use of antibiotics, especially where bacteria have become resistant to existing drugs.

In their study, published in Nature Microbiology today, ahead of World TB Day on the 24th March, the team studied genes key to bacteria’s ability to evade autophagy, a pathway that cells use to destroy themselves when they are under stress or infected.

They engineered human immune cells called macrophages from specialist stem cells called induced pluripotent stem cells, which have the ability to become any cell type in the body. They then used genome editing tools to manipulate the macrophages ability to perform autophagy. When genes key to autophagy were removed and the cells were infected with Mycobacterium tuberculosis (bacilli that cause TB), the bacterial infection took hold, replicating more within the engineered cells and causing mass host cell death.

These results are evidence for a strong role of autophagy in controlling intracellular infections like TB. If this pathway can be boosted or strengthened, it could be a new avenue for tackling antibiotic resistance, by making existing antibiotic drugs more effective or presenting an alternative to drugs in cases where bacteria have evolved resistance.

I first studied the role of autophagy in infection during my PhD, so it’s incredible to see renewed interest in this field. Using the latest technologies, we’ve been able to show a key role for this pathway in controlling infection.

As immunotherapies have harnessed the immune system to fight cancer, boosting this immune defense with a host-directed therapy, could be a valuable new tool in the fight against infections, particularly those becoming resistant to antibiotics.”

Max Gutierrez, Head of the Host-Pathogen Interactions in Tuberculosis Laboratory at Francis Crick Institute

The team also validated their results using macrophages isolated from blood samples, confirming the importance of autophagy in human defenses.

Beren Aylan, joint first author and PhD student at the Crick together with Elliott Bernard and Enrica Pellegrino, said: “Antibiotic resistance is a huge threat to our health so it’s incredibly important to understand how our bodies fight infection and where there might be room for improvement.

“TB is a great example of where targeting our own immune defenses could be really effective, because it takes a very long course of different antibiotic treatments to effectively remove the infection. Anything that can be done to more effectively remove bacteria, could also make a huge difference to the cost and accessibility of treatments.”

The team are now planning to screen for drug compounds that could be used to boost autophagy in a targeted way.

“Boosting the autophagy pathway isn’t as simple as it might seem,” adds Max. This is because all parts of the body use autophagy as a way to recycle old and damaged cells. In order to safely increase autophagy in the location of infections, we need to target the pathway in macrophages alone.”

Journal reference:

Aylan, B., et al. (2023). ATG7 and ATG14 restrict cytosolic and phagosomal Mycobacterium tuberculosis replication in human macrophages. Nature Microbiology. doi.org/10.1038/s41564-023-01335-9

SARS-CoV-2 infection damages the CD8+ T cell response to vaccination

The magnitude and quality of a key immune cell’s response to vaccination with two doses of the Pfizer-BioNTech COVID-19 vaccine were considerably lower in people with prior SARS-CoV-2 infection compared to people without prior infection, a study has found. In addition, the level of this key immune cell that targets the SARS-CoV-2 spike protein was substantially lower in unvaccinated people with COVID-19 than in vaccinated people who had never been infected. Importantly, people who recover from SARS-CoV-2 infection and then get vaccinated are more protected than people who are unvaccinated. These findings, which suggest that the virus damages an important immune-cell response, were published today in the journal Immunity.

The study was co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and led by Mark M. Davis, Ph.D. Dr. Davis is the director of the Stanford Institute for Immunity, Transplantation and Infection and a professor of microbiology and immunology at Stanford University School of Medicine in Palo Alto, California. He is also a Howard Hughes Medical Institute Investigator.

Dr. Davis and colleagues designed a very sensitive tool to analyze how immune cells called CD4+ T cells and CD8+ T cells respond to SARS-CoV-2 infection and vaccination. These cells coordinate the immune system’s response to the virus and kill other cells that have been infected, helping prevent COVID-19. The tool was designed to identify T cells that target any of dozens of specific regions on the virus’s spike protein as well as some other viral regions. The Pfizer-BioNTech vaccine uses parts of the SARS-CoV-2 spike protein to elicit an immune response without causing infection.

The investigators studied CD4+ and CD8+ T-cell responses in blood samples from three groups of volunteers. One group had never been infected with SARS-CoV-2 and received two doses of the Pfizer-BioNTech COVID-19 vaccine. The second group had previously been infected with SARS-CoV-2 and received two doses of the vaccine. The third group had COVID-19 and was unvaccinated.

The researchers found that vaccination of people who had never been infected with SARS-CoV-2 induced robust CD4+ and CD8+ T-cell responses to the virus’ spike protein. In addition, these T cells produced multiple types of cell-signaling molecules called cytokines, which recruit other immune cells—including antibody-producing B cells—to fight pathogens. However, people who had been infected with SARS-CoV-2 prior to vaccination produced spike-specific CD8+ T cells at considerably lower levels—and with less functionality—than vaccinated people who had never been infected. Moreover, the researchers observed substantially lower levels of spike-specific CD8+ T cells in unvaccinated people with COVID-19 than in vaccinated people who had never been infected.

Taken together, the investigators write, these findings suggest that SARS-CoV-2 infection damages the CD8+ T cell response, an effect akin to that observed in earlier studies showing long-term damage to the immune system after infection with viruses such as hepatitis C or HIV. The new findings highlight the need to develop vaccination strategies to specifically boost antiviral CD8+ T cell responses in people previously infected with SARS-CoV-2, the researchers conclude.  

Journal reference:

Gao, F., et al. (2023). Robust T cell responses to Pfizer/BioNTech vaccine compared to infection and evidence of attenuated peripheral CD8+ T cell responses due to COVID-19. Immunity. doi.org/10.1016/j.immuni.2023.03.005.

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.”

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.