Tag Archives: Immunity

Microbiology

Novel subset of memory B cells predicts long-lived antibody responses to influenza vaccination

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

Memory B cells play a critical role to provide long-term immunity after a vaccination or infection. In a study published in the journal Immunity, researchers describe a distinct and novel subset of memory B cells that predict long-lived antibody responses to influenza vaccination in humans.

These effector memory B cells appear to be poised for a rapid serum antibody response upon secondary challenge one year later, Anoma Nellore, M.D., Fran Lund, Ph.D., and colleagues at the University of Alabama at Birmingham and Emory University report. Evidence from transcriptional and epigenetic profiling shows that the cells in this subset differ from all previously described memory B cell subsets.

The UAB researchers identified the novel subset by the presence of FcRL5 receptor protein on the cell surface. In immunology, a profusion of different cell-surface markers is used to identify and separate immune-cell types. In the novel memory B cell subset, FcRL5 acts as a surrogate marker for positive expression of the T-bet transcription factor inside the cells. Various transcription factors act as master regulators to orchestrate the expression of many different gene sets as various cell types grow and differentiate.

Nellore, Lund and colleagues found that the FcRL5+ T-bet+ memory B cells can be detected seven days after immunization, and the presence of these cells correlates with vaccine antibody responses months later. Thus, these cells may represent an early, easily monitored cellular compartment that can predict the development of a long-lived antibody response to vaccines.

This could be a boon to the development of a more effective yearly influenza vaccine. “New annual influenza vaccines must be tested, and then manufactured, months in advance of the winter flu season,” Lund said. “This means we must make an educated guess as to which flu strain will be circulating the next winter.”

Why are vaccine candidates made so far in advance? Pharmaceutical companies, Lund says, need to wait many weeks after vaccinating volunteers to learn whether the new vaccine elicits a durable immune response that will last for months. “One potential outcome of the current study is we may have identified a new way to predict influenza vaccine durability that would give us an answer in days, rather than weeks or months,” Lund said. “If so, this type of early ‘biomarker’ could be used to test flu vaccines closer to flu season -; and moving that timeline might give us a better shot at predicting the right flu strain for the new annual vaccine.”

Seasonal flu kills 290,000 to 650,000 people each year, according to World Health Organization estimates. The global flu vaccine market was more than $5 billion in 2020.

To understand the Immunity study, it is useful to remember what happens when a vaccinated person subsequently encounters a flu virus.

Following exposure to previously encountered antigens, such as the hemagglutinin on inactivated influenza in flu vaccines, the immune system launches a recall response dominated by pre-existing memory B cells that can either produce new daughter cells or cells that can rapidly proliferate and differentiate into short-lived plasmablasts that produce antibodies to decrease morbidity and mortality. These latter B cells are called “effector” memory B cells.

“The best vaccines induce the formation of long-lived plasma cells and memory B cells,” said Lund, the Charles H. McCauley Professor in the UAB Department of Microbiology and director of the Immunology Institute. “Plasma cells live in your bone marrow and make protective antibodies that can be found in your blood, while memory B cells live for many years in your lymph nodes and in tissues like your lungs.

“Although plasma cells can survive for decades after vaccines like the measles vaccine, other plasma cells wane much more quickly after vaccination, as is seen with COVID-19,” Lund said. “If that happens, memory B cells become very important because these long-lived cells can rapidly respond to infection and can quickly begin making antibody.”

In the study, the UAB researchers looked at B cells isolated from blood of human volunteers who received flu vaccines over a span of three years, as well as B cells from tonsil tissue obtained after tonsillectomies.

They compared naïve B cells, FcRL5+ T-bet+ hemagglutinin-specific memory B cells, FcRL5neg T-betneg hemagglutinin-specific memory B cells and antibody secreting B cells, using standard phenotype profiling and single-cell RNA sequencing. They found that the FcRL5+ T-bet+ hemagglutinin-specific memory B cells were transcriptionally similar to effector-like memory cells, while the FcRL5neg T-betneg hemagglutinin-specific memory B cells exhibited stem-like central memory properties.

Antibody-secreting B cells need to produce a lot of energy to churn out antibody production, and they also must turn on processes that protect the cells from some of the detrimental side effects of that intense metabolism, including controlling the dangerous reactive oxygen species and boosting the unfolded protein response.

The FcRL5+ T-bet+ hemagglutinin-specific memory B cells did not express the plasma cell commitment factor, but did express transcriptional, epigenetic and metabolic functional programs that poised these cells for antibody production. These included upregulated genes for energy-intensive metabolic processes and cellular stress responses.

Accordingly, FcRL5+ T-bet+ hemagglutinin-specific memory B cells at Day 7 post-vaccination expressed intracellular immunoglobulin, a sign of early transition to antibody-secreting cells. Furthermore, human tonsil-derived FcRL5+ T-bet+ memory B differentiated more rapidly into antibody-secreting cells in vitro than did FcRL5neg T-betneg hemagglutinin-specific memory B cells.

Lund and Nellore, an associate professor in the UAB Department of Medicine Division of Infectious Diseases, are co-corresponding authors of the study, “A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans.”

Co-authors with Lund and Nellore are Esther Zumaquero, R. Glenn King, Betty Mousseau, Fen Zhou and Alexander F. Rosenberg, UAB Department of Microbiology; Christopher D. Scharer, Tian Mi, Jeremy M. Boss, Christopher M. Tipton and Ignacio Sanz, Emory University School of Medicine, Atlanta, Georgia; Christopher F. Fucile, UAB Informatics Institute; John E. Bradley and Troy D. Randall, UAB Department of Medicine, Division of Clinical Immunology and Rheumatology; and Stuti Mutneja and Paul A. Goepfert, UAB Department of Medicine Division of Infectious Diseases.

Funding for the work came from National Institutes of Health grants AI125180, AI109962 and AI142737 and from the UAB Center for Clinical and Translational Science.

Source:

University of Alabama at Birmingham

Journal reference:

Nellore, A., et al. (2023). A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans. Immunity. doi.org/10.1016/j.immuni.2023.03.001.

Microbiology

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

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

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.  

Source:

National Institutes of Health

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.

Microbiology

New SARS-CoV-2 Omicron XBB.1.5 variant has high transmissibility and infectivity, study finds

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Mar 20 2023Reviewed by Danielle Ellis, B.Sc.

COVID-19 has caused significant global panic after its rapid emergence more than 3 years ago. Although we now have highly effective vaccines against the SARS-CoV-2 virus, which causes COVID-19, scientists continue to study emerging SARS-CoV-2 variants in order to safeguard public health and devise global preventive strategies against emerging variants. A team led by Japanese researchers has recently discovered that the SARS-CoV-2 Omicron XBB.1.5 variant, prevalent in the Western hemisphere, has high transmissibility and infectivity.

New SARS-CoV-2 Omicron XBB.1.5 variant has high transmissibility and infectivity, study finds
New SARS-CoV-2 variant may jeopardize public health across the globe. The SARS-CoV-2 Omicron XBB.1.5 variant spreads rapidly and is more infectious than its historic precursor. Image Credit: The University of Tokyo

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for millions of deaths worldwide. Although scientists have designed novel vaccines to counter COVID-19, they are constantly on the lookout for emerging variants that can bypass vaccine resistance and potentially jeopardize global public health. A team led by Japanese researchers has recently been successful in characterizing the new SARS-CoV-2 Omicron XBB.1.5 variant, which was first detected in October 2022. Their findings were published on January 31, 2023 in volume 23 of The Lancet Infectious Diseases.​​​

Says senior author Prof. Kei Sato from the Division of Systems Virology, The Institute of Medical Science, The University of Tokyo, Japan, “Because the Omicron XBB.1.5 variant can spread more rapidly than previous variants and has a potential to cause the next epidemic surge, we should carefully monitor it to safeguard public health.”

While studying emerging variants of the SARs-CoV-2 Omicron lineage, the research team made a startling discovery: the SARS-CoV-2 Omicron XBB.1.5 variant has a novel mutation in the spike (S) protein—the protein that anchors the virus firmly to the human angiotensin converting enzyme-2 (ACE2) receptor, thus facilitating the invasion of human cells. The serine-to-proline amino acid mutation noted at residue no. 486 in the S protein is virologically concerning because of a variety of reasons.

Sharing his concerns, first author Keiya Uriu from the Division of Systems Virology, Department of Microbiology and Immunology, The University of Tokyo, Japan, says, “In late 2022, the SARS-CoV-2 Omicron BQ.1 and XBB lineages, characterized by amino acid substitutions in the S protein and increased viral fitness, had become predominant in the Western and Eastern Hemisphere, respectively. In 2022, we elucidated the characteristics of a variety of newly emerging SARS-CoV-2 Omicron subvariants. At the end of 2022, the XBB.1.5 variant, a descendant of XBB.1 that acquired the S:S486P substitution, emerged and was rapidly spreading in the USA.”

To gain mechanistic insights into the infectivity, transmissibility, and immune response associated with XBB.1.5, the team conducted a series of experiments. For instance, upon conducting epidemic dynamics analysis—statistical modeling that facilitates the analysis of the general characteristics of any epidemic—the team realized that the relative effective reproduction number (Re) of XBB.1.5 was 1.2-fold greater than that of the parental XBB.1. This indicated that an individual with the XBB.1.5 variant could infect 1.2 times more people in the population than someone with the parental XBB.1 variant. Moreover, the team also realized that, as of December 2022, XBB.1.5 was rapidly outcompeting BQ.1.1, the predominant lineage in the United States.

Co-first-author Jumpei Ito from the Division of Systems Virology, remarks, “Our data suggest that XBB.1.5 will rapidly spread worldwide in the near future.”

The team also studied the virological features of XBB.1.5 to determine how tightly the S protein of the new variant interacts with the human ACE2 receptor. To this end, the researchers conducted a yeast surface display assay. The results showed that the dissociation constant (KD) corresponding to the physical interaction between the XBB.1.5 S receptor-binding domain (RBD) and the human ACE2 receptor is significantly (4.3-fold) lower than that for XBB.1 S RBD. “In other words, the XBB.1.5 variant binds to human ACE2 receptor with very high affinity,” explains Shigeru Fujita from the Division of Systems Virology.

Further experiments using lentivirus-based pseudoviruses also showed that XBB.1.5 had approximately 3-fold higher infectivity than XBB.1. These results suggest that XBB.1.5 exhibits a remarkably strong affinity to the human ACE2 receptor, which can be attributed to the S486P substitution.

The study by Prof. Sato and his team led to another important discovery from an immunization perspective. The XBB.1.5 S protein was found to be highly resistant to neutralization antibodies elicited by breakthrough infection with the BA.2/BA.5 subvariants. In other words, patients with prior infection from the BA.2/BA.5 subvariants may not show robust immunity against XBB.1.5, increasing their chances of infection and disease.

The results of our virological experiments explain why the Omicron XBB.1.5 variant has a higher transmissibility than past variants: This variant acquired strong binding ability to human ACE2 while maintaining a higher ability to escape from neutralizing antibodies.”

​​​​​​​Yusuke Kosugi, Division of Systems Virology, Department of Microbiology and Immunology, The University of Tokyo, Japan

Contributing members of The Genotype to Phenotype Japan (G2P-Japan) Consortium conclude, “The SARS-CoV-2 Omicron XBB.1.5 variant does show enhanced transmissibility. Although few cases have been detected in the Eastern hemisphere, it could become a looming threat. Imminent prevention measures are needed.”

​​​​​​​Thanks to the research team for the early warning! Meanwhile, we must continue adopting safe practices to defend ourselves from XBB.1.5. 

Source:

The University of Tokyo

Journal reference:

Uriu, K., et al. (2023) Enhanced transmissibility, infectivity, and immune resistance of the SARS-CoV-2 omicron XBB.1.5 variant. The Lancet Infectious Diseases. doi.org/10.1016/S1473-3099(23)00051-8.

Microbiology

Review on factors related to variations in human microbiota

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Pooja Toshniwal PahariaBy Pooja Toshniwal PahariaMar 8 2023Reviewed by Aimee Molineux

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

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

Background

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

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

About the review

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

Age-related changes in the microbiota of humans

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

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

Other factors related to variations in the human microbiota composition

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

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

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

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

Conclusions

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

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

Journal reference:
Microbiology

Infections with many different types of bacteria including Streptococcus pneumonia, Listeria monocytogens, and Neisseria mengitidis can cause bacterial …

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Infections with many different types of bacteria including Streptococcus pneumonia, Listeria monocytogens, and Neisseria mengitidis can cause bacterial meningitis. It’s estimated that every year over 1.2 million cases of bacterial meningitis happen around the world, and without treatment, this deadly disease is fatal to seven of ten people who are sickened by it. Even with antibiotic treatments, three of ten patients die. Survivors are left with issues like chronic headaches, seizures, loss of vision or hearing, and other neurological consequences. New research reported in Nature has revealed how bacteria are able to penetrate the meninges that surround and protect the brain to cause bacterial meningitis. The findings have shown that bacteria use neurons to evade immunity and infect the brain, and the work may aid in the creation of new therapeutics.

A digitally-colorized SEM image depicts of Streptococcus pneumoniae bacteria (lavender), as they were being attacked by a white blood cell (pink). / Credit: CDC/ Dr. Richard Facklam

Right now, antibiotics can help eliminate the bacterial pathogens that cause this illness. But steroids are also needed to control the dangerous inflammation that can occur along with the infection. However, reducing inflammation also weakens the immune response, making it harder to get rid of the infection.

In this research, the scientists used Streptococcus pneumoniae and Streptococcus agalactiae bacteria, which can both cause bacterial meningitis in humans. They determined that when these bacteria get to the meninges, they release a toxin, which activates neurons in the meninges that sense pain. This pain neuron activation could explain why bacterial meningitis patients get horrible headaches, noted the researchers.

The activated pain neurons then release a signaling molecule called CGRP, which binds to a receptor called RAMP1 on the surface of immune cells called macrophages. Once CGRP binds to RAMP1 on macrophages, the immune cells are basically disabled, and they stop responding to bacterial infections like they normally would.

The link between CGRP and RAMP1 on macrophages also stops them from signaling to other immune cells, which allows the bacterial infection to not only penetrate the meninges but to spread infection.

This work was confirmed with the use of a mouse model that lacked the pain neurons that are activated by bacteria. Compared to mice with those neurons, the engineered mice had less severe brain infections when they were exposed to bacteria that cause meningitis. There were also lower levels of CGRP in the engineered mice compared to normal mice. The normal mice, however, had higher levels of bacteria in the meninges.

Additional experiments also showed that when mice were treated with drugs that block RAMP1, the severity of the bacterial infection was reduced. Mice treated with RAMP1 blockers were able to clear their infections faster too.

It may be possible to help the immune system clear cases of bacterial meningitis with medications that block either CGRP or RAMP1, potentially in conjunction with antibiotics. There are already drugs that can do this, and they are generally used to treat migraine.

Sources: Harvard Medical School, Nature


Carmen Leitch

Microbiology

In recent years, we have learned a lot about the crucial role gut microbes play in our health …

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In recent years, we have learned a lot about the crucial role gut microbes play in our health and well being. The extent of their influence can be surprising at times. Research has shown that gut microbes can impact the repair of tissue damage by fueling the production of a type of immune cell called Tregs, or regulatory T cells. These cells reside in various tissues and help regulate inflammation and immunity in different organs. But new work has shown that Tregs can also move around the body and respond when they are called to help fix injuries and tissue damage, such as in the muscles and liver. The findings, which used a mouse model and still have to be confirmed in humans, have been reported in the journal Immunity.

Image credit: Pixabay

There are Tregs that reside in the colon, and these cells are known to play an important role in the maintenance of gut health. The immune system in the gut has to protect us from infection while also ignoring the harmless or beneficial microbes in the gut microbiome. Gut microbes have also been known to affect Treg production. But colonic Tregs were thought to stay in the gut. In this study, the investigators found colonic Tregs among muscle cells.

First study author Bola Hanna, a research fellow in immunology at Harvard Medical School (HMS) noticed cells that looked like gut-derived Tregs among muscle tissue. The researchers wanted to known more about these mysterious cells. First, they confirmed the identity of the Tregs by analyzing gene expression and molecular characteristics. This indicated that these cells were just like colonic Tregs. Next, the investigators tagged those cells and watched as they moved around the bodies of a mouse model. The researchers assessed the antigens on these cells as well, confirming that they were equivalent to Tregs from the gut.

When a mouse model was created to lack these Tregs, and was then subjected to muscle injury, the mice had high levels of inflammation and difficulty healing. When healing did happen, it was accompanied by scarring.

In another experiment, mice were given antibiotics to reduce the levels of gut microbes. Once again, when muscle injury occurred, it took longer to heal. But if the gut microbiome was restored, normal healing commenced.

The colonic Tregs are promoting healing in muscles by reducing the levels of an inflammatory molecule called IL-17.

The investigators also found evidence of gut Tregs in different organs including the kidneys, liver, and spleen. In a mouse model of fatty liver disease, there were unusually high levels of colonic Tregs compared to healthy mice, suggesting that Tregs are influencing inflammation in a variety of tissues.

In the mouse model of fatty liver disease, symptoms got worse when the mice lacked Tregs, which also seems to confirm that colonic Tregs are playing an important role in countering the effects of inflammation due to fatty liver disease.

“Our observations indicate that gut microbes drive the production of a class of regulatory T cells that are constantly exiting the gut and act as sentries that sense damage at distant sites in the body and then act as emissaries to repair that damage,” explained senior study author Diane Mathis, a professor of immunology in the Blavatnik Institute at HMS. This work may also help scientists create therapies for fatty liver disease.

Sources: Harvard Medical School, Immunity


Carmen Leitch

Microbiology

Adult T-cell leukemia/lymphoma (ATLL) is a rare type of cancer that impacts T cells, a crucial immune cell …

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Adult T-cell leukemia/lymphoma (ATLL) is a rare type of cancer that impacts T cells, a crucial immune cell that plays an important role in fighting infection. ATLL tends to be aggressive, and can manifest in the blood as leukemia, in the lymph nodes as lymphoma, or other tissues like the skin. ATLL has been associated with human T-cell lymphotropic virus type 1 (HTLV-1) infections, although fewer than five percent of people with this virus end up developing ATLL. Right now, clinicians cannot predict which people with HTLV-1 infections will get ATLL. While some types of ATLL tumors can be surgically removed, survival prospects for these patients is not good.

Image credit: Pixabay

A recent article published in Genes & Cancer noted that even though a monoclonal antibody that can treat ATLL called mogamulizumab has recently been approved, the survival rate is still poor.

Viruses are known to change gene expression in host cells, and HTLV-1 is no different. Previous work reported in PLOS Pathogens showed that when HTLV-1 infects cells, it causes a huge number of genetic and epigenetic changes with viral proteins it generates called Tax and HBZ. These many genetic changes could be interfering with chemotherapeutics and may render them less effective, suggested researcher Tatsuro Jo of the Nagasaki Genbaku Hospital.

In the HTLV-1 genome, there is an opportunity, however. Its genome is completely different from the human genome, so the viral proteins generated during HTLV-1 infection are excellent therapeutic targets. ATLL survivors have been found to carry cytotoxic T lymphocytes that work against the HTLV-1 Tax protein. People who survive ATLL over the long term may have been able to activate strong antitumor mechanisms.

Jo added that some people who have lived for a long time after an ATLL diagnosis, and prior to the approval of mogamulizumab, had also developed herpesvirus infections. It’s been suggested that herpes infections can trigger powerful cellular immunity mechanisms.

“Although contracting herpes simplex or herpes zoster is unpleasant, the mechanism by which these herpesvirus infections can produce a therapeutic effect on refractory ATLL via the activation of the host’s cellular immunity is extremely interesting and worth further study,” said Jo.

Sources: Impact Journals LLC, Genes & Cancer


Carmen Leitch

Microbiology

Though the COVID-19 pandemic has waned, SARS-CoV-2 is still with us, and we still need diagnostic tests. Scientists …

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Though the COVID-19 pandemic has waned, SARS-CoV-2 is still with us, and we still need diagnostic tests. Scientists have been improving those tests in several ways. Researchers are developing a test that can rapidly diagnose new COVID-19 infections within hours of exposure. A combination flu and COVID-19 test has recently been approved by the US Food and Drug Administration (FDA) and is now available to consumers for use at home. A COVID-19 home test with greater sensitivity has also been created and will hopefully reach the market soon.

Image credit: Pixabay

Typical COVID-19 tests identify viral particles in swabs of the nostrils, throat, and/or cheeks. But those tests are best used during certain windows, and they can miss active infections when there isn’t much viral material available because a person is asymptomatic, or the infection has not yet set in and begun to replicate robustly. A totally new type of test uses a different approach, and aims to detect the immune response to the virus. The work has been published in Cell Reports Methods.

A viral infection activates the expression of a variety of immune genes, which are transcribed into mRNA molecules. The test detects certain levels of those mRNA molecules. The researchers used blood samples collected during the COVID-19 pandemic to validate their results; the test detected COVID-19 infections, even in asymptomatic people, with 98.4 percent accuracy.

More work is still needed to improve the test. For example, it uses blood samples and not nasal swabs. The scientists also need to verify that it can distinguish between different types of viral infections, like COVID-19 and the flu. But the researchers are hopeful that the diagnostic test will be available in the near future.

A combination flu and COVID-19 test is already on the market. The FDA recommends the test for anyone with symptoms of a respiratory tract infection symptoms. It’s called the Lucira COVID-19 & Flu Home test. It does not require a prescription, requires nasal swabs that can be collected by the user at home, and results are available in about 30 minutes.

While samples have to be collected by an adult, the test can be used on anyone older than 2. There is a small risk of false negatives, noted the FDA, so if respiratory infection symptoms exist and the test is negative, people may still want to follow up with their healthcare provider.

Scientists have also developed a much more sensitive test for COVID-19 that can be used at home. The work was reported in ACS Infectious Diseases.

At-home tests change color when an antibody-linked reporter molecule latches onto viral particles in a sample. But that color change is very faint when few viral particles are present. PCR-based tests are good for disease detection because only very small amounts of viral material have to be present; they are then amplified by PCR. But special equipment is needed for PCR.

This new, sensitive test has added an amplification step to a test that can be used at home. A hybridization chain reaction (HCR) boosts the signal of reporter molecules instead. The viral protein gets tagged with a DNA molecule, which can act as a scaffold that more reporter molecules can bind to. Thus, every viral particle triggers the emission of a much stronger signal.

When the sensitive test was compared to tests that are on the market, it was 2.5 times more sensitive than the best, and 100 times more sensitive than the worst. The researchers are now working to get the new test to the market.

Sources: California Institute of Technology, ACS Infectious Diseases, The Associated Press, Simons Foundation, Cell Reports Methods


Carmen Leitch

Microbiology

Long COVID still affects many people who had a case of COVID-19; even people who had mild cases …

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Long COVID still affects many people who had a case of COVID-19; even people who had mild cases and were not hospitalized are at risk for the chronic disorder. Scientists and clinicians are still learning about the illness, which causes a wide range of symptoms and happens for unknown reasons. There are several hypotheses, however, and the disorder may also arise in different people for different reasons. New research has suggested that long COVID happens because particles of SARS-CoV-2, the virus that causes COVID-19, hide away in parts of the body, and the immune system becomes overactivated trying to eliminate them. The study has been reported in PLOS Pathogens.

Colorized scanning electron micrograph of a cell (brown) infected with the Omicron strain of SARS-CoV-2 virus particles (purple), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

Symptoms of long COVID can include fatigue, brain fog, cough, shortness of breath, and chest pain, and these symptoms last more than four weeks after the acute phase of COVID-19. The illness is thought to impact about 20 percent of people who get COVID, noted Brent Palmer, Ph.D., an associate professor at the University of Colorado School of Medicine.

In this study, the researchers followed forty COVID-19 patients; twenty of them totally eliminated the infection and twenty developed long COVID, also known as  post-acute sequelae of COVID (PASC). The investigators used blood and stool samples from the study volunteers to identify T cells that were specific to COVID-19 and remained active after the initial infection was over.

These cells were then incubated with bits of the virus, and the scientists were able to see how frequently CD4 and CD8 T cells were reacting by generating cytokines. They found that long COVID patients carried levels of cytotoxic CD8 T cells that were as much as 100 times higher compared to people who cleared the infection.

Palmer also studies HIV infection, and he was astonished to find that about 50 percent of T cells were still directed against COVID-19 six months after their initial infection. “That’s an amazingly high frequency, much higher than we typically see in HIV, where you have ongoing viral replication all the time,” he added. “These responses were in most cases higher than what we see in HIV.”

CU pulmonologist Sarah Jolley, MD was a study co-author who obtained pulmonary data for the study volunteers. The researchers found that pulmonary function decreased as the level of COVID-19-specific T cells increased.

“That showed a really strong connection between these T cells that were potentially driving disease and an actual readout of disease, which was reduced pulmonary function. That was a critical discovery.”

The researchers have suggested that long COVID is drive by the immune system, which is increasing inflammation as it attempts to remove residual SARS-CoV-2 particles that cannot be detected with a nasal swab, but nonetheless remain. Palmer noted that some autopsies of COVID-19 patients have revealed the virus in many organs including the lungs, gut and kidney.

 

Additional work by Palmer and colleagues was reported in the journal Gut; this study indicated that the composition of the gut microbiomes of long COVID patients reflects an elevation of inflammatory markers. There may also be a link between the gut microbiome and the inflammation that is observed in long COVID, noted the researchers.

Palmer added that some studies have shown that antiviral medications like Paxlovid, or doses of vaccine may help relieve the symptoms of long COVID patients. This may happen because their immune systems are being given enough of a stimulatory bump to finally remove the infection, and it would show that a hidden reservoir of virus likely exists in these patients.

Sources: CU Anschutz Medical Campus, PLOS Pathogens, Gut


Carmen Leitch

Microbiology

Differences in gut microbiome diversity attributed to dietary patterns in children with obesity

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Dr. Chinta SidharthanBy Dr. Chinta SidharthanFeb 16 2023Reviewed by Benedette Cuffari, M.Sc.

In a recent study published in Microbiology Spectrum, researchers found that differences in the dietary patterns of children with normal weight and those who were overweight or obese contributed to variations in the gut microbiome diversity, virulence factors of gut bacteria, and metabolic function.

Study: Virulence factors of the gut microbiome are associated with BMI and metabolic blood parameters in children with obesity. Image Credit: Africa Studio / Shutterstock.com

Study: Virulence factors of the gut microbiome are associated with BMI and metabolic blood parameters in children with obesity. Image Credit: Africa Studio / Shutterstock.com

Background

A growing body of evidence indicates that gut microbiota has a significant role in various aspects of host metabolism, including digestion, harvesting of energy, and induction of low-grade inflammation. In addition, the genetic factors of the host, as well as other characteristics such as age, diet, immunity, and gender, influence the gut microbiome composition.

Research shows that bacterial diversity in the gut and the individual’s functional capacity vary between those with normal weight and obese individuals. Gut microbiome profile variations have also been linked to metabolic disorders, lipid accumulation, and inflammation.

Lipogenesis in the liver and the regulation of appetite through hormones are also associated with gut microbiome genes.

Aside from its role in adipogenesis, superoxide reduction, and the metabolism of vitamins, gut microbiota also regulates innate immunity and the systemic, low-grade inflammatory state that can contribute to fat deposition and obesity. Therefore, Dysbiosis, which is the imbalance of gut microbiota, combined with diet, likely has a significant role in the development of obesity.

About the study

In the present study, researchers conducted a cross-sectional analysis of data from 45 children between the ages of six and 12 to determine the association between gut microbiota and obesity.

Questionnaires were used to obtain information on dietary frequencies, gender, age, and body mass index (BMI). Based on the World Health Organization (WHO) z-scores, in which BMI is adjusted for gender and age, the children were classified into two categories of overweight and obese (OWOB) and normal weight (NW).

Data from food frequency questionnaires were used to classify the dietary habits of children into two nutritional patterns. To this end, Pattern 1 was characterized by complex carbohydrates and proteins, whereas Pattern 2 comprised simple carbohydrates and saturated fats.

Shotgun metagenomics was used to assess the taxonomic diversity of the gut microbiota and metabolic capacity from genomic deoxyribonucleic acid (DNA) extracted from fecal samples. Clade-specific markers were used for the taxonomic and functional assessment of the gut bacteria. Additionally, reverse Simpson and Shannon diversity indices were calculated.

The virulence factor database was used to screen for virulence factor genes, whereas multivariate linear modeling was used to determine the association between the taxa, virulence factors, and function of gut microbes and covariates of diet, serology, and anthropometric measurements.

Study findings

Significant differences between the alpha and beta diversity of the gut microbiota were observed between the children in the NW and OWOB groups, thus suggesting that specific phyla of bacteria contribute to higher levels of energy harvest.

Furthermore, species such as Ruminococcus species, Victivallis vadensis, Mitsuokella multacida, Alistipes species, Clostridium species, and Acinetobacter johnsonii were linked to healthier metabolic parameters.

In contrast, an increase in the abundance of bacteria such as Veillonellaceae, Lactococcus, Fusicatenibacter saccharivorans, Fusicatenibacter prausnitzii, Eubacterium, Roseburia, Dialister, Coprococcus catus, Bifidobacterium, and Bilophila was identified in children with pro-inflammatory conditions and obesity.

Bacteria such as Citrobacter europaeus, Citrobacter youngae, Klebsiella variicola, Enterococcus mundtii, Gemella morbillorum, and Citrobacter portucalensis were associated with higher lipid and sugar intake, as well as higher blood biochemistry values and anthropometric measurements.

Diets high in fats and simple carbohydrates have been associated with the abundance of Citrobacter and Klebsiella species in the gut. Moreover, previous studies have indicated that these bacterial species are potential markers of inflammation, obesity, and an increase in fasting glucose.

The metabolism of menaquinones and gamma-glutamyl was negatively associated with BMI. Furthermore, the microbiomes of children in the NW group preserved a more consistent alpha diversity of virulence factors, while OWOB microbiomes exhibited a dominance of virulence factors.

Differences in the metabolic capacities pertaining to biosynthesis pathways of vitamins, carriers, amino acids, nucleotides, nucleosides, amines, and polyamines, as well as the degradation of nucleotides, nucleosides, and carbohydrate-sugars, were also found between the NW and OWOB groups.

Conclusions

Dietary profiles and the diversity of gut microbiota were found to be interconnected and associated with changes in metabolic parameters, the dominance of virulence factors, and obesity. Changes in gut microbiome diversity and relative abundance have been linked to obesity, inflammatory responses, and metabolic disorders.

Taken together, the study findings suggested that the prevalence of virulence factors, as well as the metabolic and genetic roles of gut microbiota in increasing inflammation, can help identify individuals at an increased risk of childhood obesity.

Journal reference:
  • Murga-Garrido, S. M., Ulloa-Pérez, E. J., Díaz-Benítez, C. E., et al. (2023). Virulence factors of the gut microbiome are associated with BMI and metabolic blood parameters in children with obesity. Microbiology Spectrum. doi:10.1128/spectrum.03382-22