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Thursday, September 22, 2022

SARS-CoV-2 infects fat tissue and creates inflammatory storm cloud

 Is SARS-CoV-2 hiding in your fat cells?

A study by Stanford Medicine investigators shows that SARS-CoV-2 can infect human fat tissue. This phenomenon was seen in laboratory experiments conducted on fat tissue excised from patients undergoing bariatric and cardiac surgeries, and later infected in a laboratory dish with SARS-CoV-2. It was further confirmed in autopsy samples from deceased COVID-19 patients.

Obesity is an established, independent risk factor for SARS-CoV-2 infection as well as for the patients' progression, once infected, to severe disease and death. Reasons offered for this increased vulnerability range from impaired breathing resulting from the pressure of extra weight, to altered immune responsiveness in obese people.

But the new study provides a more direct reason: SARS-CoV-2, the virus that causes COVID-19, can directly infect  (which most of us refer to as just plain "fat"). That, in turn, cooks up a cycle of  within resident fat cells, or , and causes pronounced inflammation in immune cells that hang out in fat tissue. The inflammation converts even uninfected "bystander" cells within the tissue into an inflammatory state.

"With 2 of every 3 American adults overweight and more than 4 in 10 of them obese, this is a potential cause for concern," said Tracey McLaughlin, MD, professor of endocrinology.

The findings are described in a study published online Sept. 22 in Science Translational Medicine. McLaughlin and Catherine Blish, MD, Ph.D., professor of infectious diseases, are the study's senior authors. Lead authorship is shared by former postdoctoral scholar Giovanny Martínez-Colón, Ph.D., and graduate student Kalani Ratnasiri.

The fat-COVID-19 connection

Obesity is defined medically as having a  (weight in kilograms divided by the square of height in meters) of 30 or greater. Someone with a BMI of 25 or greater is defined as being overweight. Obese individuals are up to 10 times as likely to die from COVID-19, McLaughlin said, but increased risk for poor outcomes of SARS-CoV-2 infection begins at BMIs as low as 24.

"Fat tissue's susceptibility to SARS-CoV-2 infection may be playing a role in making obesity a COVID-19 risk factor," said Blish, who is the George E. and Lucy Becker Professor in Medicine. "Infected fat tissue pumps out precisely the inflammatory chemicals you see in the blood of severe COVID patients. It's reasonable to infer that having a lot of infected fat could contribute to the overall inflammatory profile of severely ill COVID-19 patients."

The scientists obtained samples of fat tissue from various locations in the bodies of 22 patients undergoing bariatric or cardiothoracic surgery at the Stanford Medicine Bariatric Surgery and Cardiothoracic Surgery clinic. Then, in a secure facility, the researchers infected the samples with a solution containing SARS-CoV-2 or, as a control, a SARS-CoV-2-free solution. Rigorous experiments showed that the virus could infect and replicate in fat cells, exit the cells and cause new infections in other cells.

Fat tissue contains not only fat cells but also a wide variety of immune cells, including a type called macrophages. These cells (whose name derives from two Greek words meaning "big eaters") carry out a number of actions ranging from tissue repair and general garbage cleanup to fierce attacks on perceived pathogens—sometimes producing substantial collateral damage to normal tissue in the process.

The researchers identified a subset of macrophages in fat tissue that become infected by SARS-CoV-2, although only fleetingly. SARS-CoV-2 infection of these macrophages is abortive: It produces no viable viral progeny. But it does induce a major mood change in the macrophages.

"Once infected, these macrophages not only become inflamed themselves but also secrete substances that call in more inflammatory immune cells, in addition to inducing inflammation in uninfected neighboring 'bystander cells,'" Blish said.

Fat tissue surrounds our hearts, guts, kidneys and pancreases, which can be adversely affected by tissue inflammation. Ominously, the scientists found infection capable of driving inflammation in virtually every SARS-CoV-2-infected fat-tissue sample they collected and analyzed.

Genetic material encoding SARS-CoV-2 was almost invariably present in fat tissue from various bodily regions of eight patients who had died of COVID-19. Examining tissue from two other deceased COVID-19 patients, the team saw an infiltration of inflammatory  adjacent to infected fat cells in epicardial fat.

"This was of great concern to us, as epicardial fat lies right next to the heart muscle, with no physical barrier separating them," McLaughlin said. "So, any inflammation there may directly affect the heart muscle or coronary arteries."

Missing ACE2

Oddly, ACE2—the cell surface molecule that's been implicated as the cardinal receptor for SARS-CoV-2—appeared to play little or no role in the ability of the virus to infect fat cells.

The method by which SARS-CoV-2 gains entry to  and  in fat tissue remains mysterious. The established primary mode of entry occurs when the virus ties up with a protein called ACE2 that sits on cell surfaces in numerous bodily tissues. Although ACE2 carries out important, legitimate functions, the virus doesn't care what ACE2 does for a living—it considers this cell-surface protein a mere docking station.

This was the height of irony for McLaughlin and Blish, who initiated the study because they'd seen reports suggesting, although not proving, that ACE2 might be present in fat tissue. (Nobody had claimed to have sighted the protein itself, Blish added.)

But the researchers found, to their surprise, that ACE2 was virtually nonexistent on cells present in fat tissue.

"It's highly unlikely the virus is entering through ACE2, because we couldn't detect the functional protein in adipose tissue," said Blish.

That means clearing SARS-CoV-2 from  could require new drugs. Monoclonal antibody therapies licensed for COVID-19, for instance, generally work by interfering with ACE2/SARS-CoV-2 interaction.

Fat tissue's potential to serve as a reservoir where SARS-CoV-2 can hide out also raises the possibility that it could contribute to the enduring post-infection symptoms collectively called long COVID, a hypothesis that McLaughlin and Blish are beginning to explore.

Researchers from the University of Tübingen, University of Basel, Beth Israel Deaconess Medical Center in Boston and Cantonal Hospital Baselland in Liestal, Switzerland contributed to the work.

Explore further

Scientists discover a novel mechanism leading to the inflammatory cytokine storm in COVID-19

More information: Kathryn H. Morelli et al, MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy, Science Translational Medicine (2022). DOI: 10.1126/scitranslmed.abn2375

Newly discovered COVID-like virus could infect humans, resist vaccines

 A recently discovered virus in a Russian bat that is similar to SARS-CoV-2, the virus behind COVID-19, is likely capable of infecting humans and, if it were to spillover, is resistant to current vaccines.

A team lead by researchers in Washington State University's Paul G. Allen School for Global Health found  from the bat virus, named Khosta-2, can infect  cells and is resistant to both the  and serum from individuals vaccinated for SARS-CoV-2. Both Khosta-2 and SARS- CoV-2 belong to the same sub-category of coronaviruses known as sarbecoviruses.

"Our research further demonstrates that sarbecoviruses circulating in wildlife outside of Asia—even in places like western Russia where the Khosta-2 virus was found—also pose a threat to global health and ongoing vaccine campaigns against SARS-CoV-2," said Michael Letko, WSU virologist and corresponding author of the study published in the journal PLoS Pathogens.

Letko said the discovery of Khosta-2 highlights the need to develop universal vaccines to protect against sarbecoviruses in general, rather than just against known variants of SARS-CoV-2.

"Right now, there are groups trying to come up with a  that doesn't just protect against the next variant of SARS-2 but actually protects us against the sarbecoviruses in general," Letko said. "Unfortunately, many of our current vaccines are designed to specific viruses we know infect human cells or those that seem to pose the biggest risk to infect us. But that is a list that's everchanging. We need to broaden the design of these vaccines to protect against all sarbecoviruses."

While hundreds of sarbecoviruses have been discovered in recent years, predominantly in bats in Asia, the majority are not capable of infecting human cells. The Khosta-1 and Khosta-2 viruses were discovered in Russian bats in late 2020, and it initially appeared they were not a threat to humans.

"Genetically, these weird Russian viruses looked like some of the others that had been discovered elsewhere around the world, but because they did not look like SARS-CoV-2, no one thought they were really anything to get too excited about," Letko said. "But when we looked at them more, we were really surprised to find they could infect human cells. That changes a little bit of our understanding of these viruses, where they come from and what regions are concerning."

Letko teamed with a pair of WSU faculty members, first author viral ecologist Stephanie Seifert and viral immunologist Bonnie Gunn, to study the two newly discovered viruses. They determined Khosta-1 posed low risk to humans, but Khosta-2 demonstrated some troubling traits.

The team found that like SARS-CoV-2, Khosta-2 can use its spike protein to infect  by attaching to a receptor protein, called angiotensin converting enzyme 2 (ACE2), found throughout . They next set out to determine if current vaccines protect against the new virus.

Using serum derived from  vaccinated for COVID-19, the team saw that Khosta-2 was not neutralized by current vaccines. They also tested serum from people who were infected with the omicron variant, but the antibodies, too, were ineffective.

Fortunately, Letko said the new virus is lacking some of the genes believed to be involved in pathogenesis in humans. There is a risk, however, of Khosta-2 recombining with a second virus like SARS-CoV-2.

"When you see SARS-2 has this ability to spill back from humans and into wildlife, and then there are other viruses like Khosta-2 waiting in those animals with these properties we really don't want them to have, it sets up this scenario where you keep rolling the dice until they combine to make a potentially riskier ," Letko said.

In addition to Letko, Seifert and Gunn, co-authors on this study include Shuangyi Bai and Stephen Fawcett of WSU as well as Elizabeth Norton, Kevin Zwezdaryk and James Robinson of Tulane University.

Explore further

From computer to benchtop: Researchers find clues to new mechanisms for coronaviruses infections

More information: An ACE2-dependent Sarbecovirus in Russian bats is resistant to SARS-CoV-2 vaccines, PLoS Pathogens (2022). DOI: 10.1371/journal.ppat.1010828

Identifying 'safe harbor' for gene therapies

 Scientists at St. Jude Children's Research Hospital have created a tool that can find safe places to introduce genes into human DNA. The tool is an early step in the process to improve the safety and efficacy of gene and cell therapies. The work appears today in Genome Biology.

"We've created the Google Maps of editing the genome," said co-corresponding author Yong Cheng, Ph.D., St. Jude Department of Hematology. "With this tool, we provide a new approach to identify places to safely integrate a gene cassette. We created step-by-step directions, so you can follow the steps and easily find safe harbor sites in specific tissues."

Gene therapy, where a patient is given a functional copy of a dysfunctional gene, has shown success in curing certain genetic disorders. However, the field has encountered safety issues, including the inadvertent activation of an oncogene that led to cancer in some patients. In response, the field has searched for "safe harbor sites"—places in the genome where a gene can be inserted without causing cancer or other problems. The scientists created a pipeline that uses genomic and  from specific tissue, such as blood cells, to find safe harbor sites.

A novel way to find safe harbor sites

The tool compares the DNA sequences that are highly variable between healthy people, using data from the 1000 Genomes Project. If a region of DNA is often deleted or inserted in healthy people, the researchers reasoned that it could likely also be altered safely by a gene therapy.

"Our method is a new way to identify genomic safe harbor sites in a tissue-specific manner," Cheng said. "Nobody has tried it from this angle. Our first step was to find the genomic loci that show a high frequency of insertion or deletion among healthy individuals."

If DNA in a single cell were a string, it would be two meters long. But in addition to the linear sequence, DNA can loop into complex 3D structures using chromatin, the proteins associated with DNA, to fit within a cell. Just like a string, DNA can have loops that affect its function. The St. Jude tool considers the presence of these loops and other structures when searching for accessible safe harbor sites.

"Our tool assesses the 3D structure of DNA, because human DNA is not a one-dimensional linear structure, it's actually 3D," Chen said. "So, parts of DNA may be far away in the linear sequence of DNA but may physically be next to each other because of the looping of the 3D structure. In that case, the 3D proximity is more important than the linear distance."

Balancing safety and therapeutic gene expression

"Safe gene therapy requires two things," said Cheng. "Number one, maintaining high expression of the new gene. And number two, the integration needs to have minimal effects on the normal human genome, which is a major concern for people performing gene therapy."

The scientists found that the genes placed in safe harbor sites identified by their tool maintained their expression over time. The researchers also showed that if they put a gene into one of the safe harbor sites identified by their tool, it affected nearby genes less than a classic safe harbor site.

The tool, Genomics and Epigenetic Guided Safe Harbor mapper (GEG-SH mapper), is freely available on Github.

Explore further

AAV vector integration into CRISPR-induced DNA breaks

More information: Dewan Shrestha et al, Genomics and epigenetics guided identification of tissue-specific genomic safe harbors, Genome Biology (2022). DOI: 10.1186/s13059-022-02770-3

Awakening 'dormant' cells to fight cancer

 The advent of small-molecule targeted therapies, a decade ago, revolutionized the treatment of metastatic melanoma, provided that the tumors carry the mutations to respond to these treatments. However, despite a remarkable initial response that can be seen in a majority of patients, most of them will undergo relapse even after spectacular initial responses. These relapses are due to "dormant" persistent cells, unresponsive to treatment. A team from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) has shown that these cells under-express a protein called HuR. By deciphering the mechanism of this insufficient expression and by targeting it with an enzyme inhibitor, this team has succeeded in reducing the therapeutic resistance of all melanoma cells. These results, published in Biochemical and Biophysical Research Communications, open new therapeutic avenues against metastatic melanoma and other types of solid cancers.

Melanoma is one of the most dangerous skin cancers. Potentially very aggressive, it develops from melanocytes, the cells responsible for skin pigmentation. The initial tumor can be superficial with a good prognosis upon removal, it can also be deeper and become metastatic, i.e. migrate to other organs in the body.

For the last ten years, thanks to the advent of the so-called small-molecule targeted therapies -- drugs that inhibit a precise mechanism within the tumor to fight it -- half of the metastatic melanomas that carry a genetic signature making them sensitive to these drugs, can be treated effectively, sometimes even be eradicated. "However, despite such spectacular initial responses, 80% of patients will suffer recurrences, and these recurrences will often occur in the same initially affected sites," explains Rastine Merat, researcher in the Department of Medicine at the UNIGE Faculty of Medicine and head of the Onco-dermatology Unit at the HUG.

A protein regulating cell division is involved

This phenomenon is called ''adaptive resistance'': certain cancer cells adapt to the drugs used to fight them and lead to a resurgence of the disease. This happens even when the metastases -- and therefore the cells that make these tumors -- seem to have completely disappeared. "This is explained by the persistence, after treatment, of small residues of so-called 'dormant' malignant cells that conventional radiology tools are unable to detect," says Rastine Merat. "The particularity of these cells, in addition to being invisible, is that they proliferate slowly. This characteristic helps the cells to escape therapy, even during the initial treatment."

Previously conducted research has shown that in slow-proliferating cells, a protein that among other things regulates the expression of many genes that control cell division -- the HuR protein -- is insufficiently expressed. This is in contrast with rapidly proliferating cells in which this protein is highly expressed. In a research work published in 2019, Rastine Merat and his team had established the link between the insufficient expression of this protein and the melanoma cells' capacity to resist to a targeted therapy. In their recent research, they have uncovered a specific mechanism involved in the insufficient expression of this protein in the "dormant" cells that can be targeted with drugs.

Inhibiting enzymes to prevent recurrence

"In the cells, messenger RNAs play a central role in protein production. In the minority of cells in which HuR is insufficiently expressed, we found that the messenger RNAs of HuR were trapped by some other proteins. This is at least one of the mechanisms that causes HuR insufficient expression." By using a chemical compound to inhibit two kinases -- enzymes -- involved in this mechanism, the UNIGE team managed to prevent HuR insufficient expression, reducing the ability of all melanoma cells to resist to treatment.

"The great difficulty in carrying out this work was to work on this type of cells, which are difficult to detect and analyze because of their small number and the fact that the state of insufficient expression of HuR protein is dynamic and reversible at any time for any cells; i.e. at any time the same cells can start to proliferate and flip to a state of high expression of this protein," explains the researcher. To do this, "we paradoxically overexpressed this protein in melanoma cells. This allowed us to make the mechanisms at play more easily detectable." This discovery opens new perspectives in the treatment of melanoma, but not only. "Melanoma is a model cancer: if we understand it, we can understand many other types of solid cancers," explains Rastine Merat.

For the researcher and his team, "the next step will be to encourage the pharmaceutical industry to optimize the inhibitors of the identified kinases, -- to improve their stability and bioavailability -- which is something pharmaceutical drug companies know how to do nowadays in a very systematic way, at least for this type of target," concludes Rastine Merat.

Story Source:

Materials provided by Université de GenèveNote: Content may be edited for style and length.

Journal Reference:

  1. Fanny Noulet, Rastine Merat. Inhibition of the DAPKs-L13a axis prevents a GAIT-like motif-mediated HuR insufficiency in melanoma cellsBiochemical and Biophysical Research Communications, 2022; 626: 21 DOI: 10.1016/j.bbrc.2022.07.086

A quick test kit to determine a person's immunity against COVID-19 and its variants

 A team of scientists from the Singapore-MIT Alliance for Research and Technology (SMART), MIT's research enterprise in Singapore,and Nanyang Technological University, Singapore (NTU Singapore) has developed a quick test kit that can tell if a person has immunity against COVID-19 and its variants, based on the antibodies detected in a blood sample.

Different from ART test kits -- which look for the presence of viral proteins produced during a COVID-19 infection to determine if a person is infected -- this rapid point-of-care test kit is a serology test that measures antibodies made by the patient. It requires a drop of blood and takes just 10 minutes to show results, as compared to the 24 to 72 hours required for conventional laboratory testing.

The test kit detects the levels of neutralising antibodies against SARS-COV-2, the virus causing COVID-19, and its variants such as Delta and Omicron, and can be easily adapted for new variants of concern and other diseases in the future.

Using a paper-based assay that is coated with chemicals that bind to antibodies in the blood sample, the test kit is low-cost, fast and has up to 93 per cent accuracy. It paves the way for personalised vaccination strategies, where people are only given vaccinations and booster shots when necessary, depending on their variance in antibody levels and immune response.

The findings were published in the scientific journal Microbiology Spectrum by the joint team led by SMART's Antimicrobial Resistance (AMR) Interdisciplinary Research Group (IRG) and NTU's School of Biological Sciences, in collaboration with Singapore's National University Hospital (NUH) and National Centre for Infectious Diseases (NCID), and Massachusetts Institute of Technology (MIT).

The work is funded by the National Research Foundation (NRF) Singapore under its Campus for Research Excellence and Technological Enterprise (CREATE) programme. It is also supported by Singapore's National Medical Research Council (NMRC), under its COVID-19 Research Fund, and National Health Innovation Centre (NHIC), under its COVID-19 Gap funding grant.

Fast and accurate tests to overcome challenges

Having an accurate and rapid serology test can enable governments and healthcare organisations to effectively manage limited vaccine resources, and address vaccine hesitancy, particularly concerning multiple booster doses.

Vaccination has been an integral component of public health strategies to tackle the COVID-19 pandemic, with 12.6 billion doses across 184 countries administered as of 9 Sep 2022. Vaccines reduced the COVID-19 death toll by 63 per cent within the first year of their rollout, preventing an estimated 19.8 million deaths worldwide, according to a report by the World Health Organisation (WHO).

In Singapore, the Ministry of Health (MOH) estimated in February 2022 that COVID-19 vaccines had prevented 8,000 deaths during the wave of the Delta variant in 2021, as well as preventing an estimated 33,000 severe cases and 112,000 hospitalisations.

However, a clinical study by the joint research team has shown that the protection offered by currently available vaccines steadily declines over three months, with varying degrees of decline across individuals. The study showed that after three months of a booster shot, the neutralising antibody (NAb) response against wildtype and Delta still remained high at medians of 91.8 per cent, while medians against Beta and Gamma had dropped to 82.7 and for Omicron, a large drop to 70.7 per cent, down from 92.9 per cent.

The emergence of novel variants with much higher transmissibility than the wild-type virus -- such as Delta and Omicron -- has exacerbated the issue of using mRNA vaccines developed based on the wildtype virus to boost immunity, especially when some current vaccines are showing reduced protection against these novel variants of concern (VoC).

In addition, vaccine hesitancy remains among limited subsets of the population, where people are wary of taking the vaccine or booster shots due to fear of side effects, further compounding the difficulty in employing a widespread vaccination strategy to build herd immunity.

To address vaccine hesitancy and efficacy of vaccination against novel variants, a personalised vaccination approach could be more effective, one which offers booster doses to individuals assessed to be more at risk, such as healthcare workers and the elderly.

For a personalised approach to be effective, healthcare workers need to be able to quickly evaluate the level of NAb response against variants at the individual level, using an easy-to-use point-of-care test kit in clinics, hospitals or vaccination centres.

Corresponding author of the paper, Professor Peter Preiser, Co-Lead Principal Investigator at SMART AMR and Associate Vice President for Biomedical and Life Sciences at NTU Singapore said: "Our team's work in the development of a rapid test kit has given us valuable insights into vaccine effectiveness and protection longevity. Our study proves that our new test kit can be a powerful tool, allowing healthcare organisations to screen people and determine their vaccination needs, especially against the current and upcoming variants. This will help allay some people's fears that they will be 'over-vaccinated with a booster', since the results will inform them accurately if they are well-protected against COVID-19 or not."

Dr Hadley Sikes, SMART AMR Principal Investigator, Associate Professor at MIT and co-corresponding author of the paper added, "Over the course of the pandemic, several large studies have shown that NAb levels against the dominant variant at the time of the study are a reliable indicator of protection from infection. Some segments of the population have low tolerance for risk of infection. The test kit we developed can provide valuable, individualised information about how quickly or how slowly a person's antibodies levels have fallen, allowing them to stay informed of their health and, whenever required, get a necessary booster dose to protect themselves."

Proven effectiveness of antibody test kit

In their research paper, the team describes a clinical study of their cellulose pulled-down virus neutralisation test kit (cpVNT), a neutralising antibody blood test designed to assess an individual's immunoprotective profile against SARS-CoV-2 and its variants.

With a drop of finger prick blood, the test kit can evaluate an individual's neutralising antibody level against a specific COVID-19 variant within 10 minutes, making this an efficient, low-cost, and easy-to-use tool that will enable large-scale testing and can be widely deployed anywhere as part of a personalised vaccination strategy.

The test reveals the individual's level of neutralising antibodies, which can then inform a person when a booster should be taken, and how cautious they should be about potential transmission before it is taken.

It can be administered by a layperson without medical training and does not require any specialised laboratory equipment, paving the way for large-scale testing of vulnerable subsets of the population such as the elderly.

Co-first author of the paper and former Postdoctoral Associate at SMART AMR Hoi Lok Cheng said, "This is an exciting breakthrough for us, and a continuation of our long-running work to develop efficient, low-cost, and easy-to-use NAb tests to combat the COVID-19 pandemic. As a quantitative test that can detect NAb levels specific to key variants such as Delta and Omicron, the cpVNT has given us valuable insights into the effectiveness of various vaccines vis-à-vis variants of concern. This test kit will also prove integral to a more personalised vaccination approach that will benefit higher-risk individuals such as the elderly and healthcare workers. Individuals from these communities can have their immuno-protective profile assessed on a regular basis via the cpVNT, allowing them to know when a booster dose may be appropriate or necessary. Furthermore, this test can be easily adapted to test for novel SARS-CoV-2 variants that may emerge in the future."

This research builds on years-long body of work by the SMART team. In a paper published in the medical and public health journal Communications Medicine, the team laid out the foundation for a cellulose-based vertical-flow test to detect neutralising antibodies against SARS-CoV-2.

A separate paper published in premier chemical engineering journal Bioengineering and Translational Medicine discussed the test's effectiveness against other methods such as the pseudovirus-based virus neutralisation test (pVNT) and surrogate virus neutralisation test (sVNT), with favourable results.

Using clinical samples (including both whole blood and plasma) and the World Health Organisation International Standard and Reference Panel for anti-SARS-CoV-2 antibody, the team established that a whole-blood test such as the cpVNT could be as informative as a plasma-only test.

As plasma- or serum-based tests require laboratory equipment to process the blood sample as well as higher quantities of blood samples to be taken, the cpVNT is therefore more resource-efficient and less invasive.

Furthermore, the cpVNT's viability demonstrates that neutralising antibody and point-of-care tests can be successfully performed using such a format and protocol -- paving the way for further development and innovation of this platform to tackle other diseases.

Further development of the test kit is underway to meet the necessary regulatory approvals and manufacturing standards for public use. The team that has developed the tests at SMART has also spun off a biotech startup, Thrixen, which is developing the test into a commercially ready product.

Key development of the rapid test was done at SMART AMR together with NTU scientists, who helped in the design of the study, providing specific reagent supplies and clinical sample collections. NUH and NCID had provided clinical sample supplies and consultation on medical use of the test, while MIT supervised the project.

Story Source:

Materials provided by Singapore-MIT Alliance for Research and Technology (SMART)Note: Content may be edited for style and length.

Journal Reference:

  1. Hoi Lok Cheng, Sing Mei Lim, Huan Jia, Ming Wei Chen, Say Yong Ng, Xiaohong Gao, Jyoti Somani, Sharmila Sengupta, Dousabel M. Y. Tay, Patrina W. L. Chua, Abirami R., Sharon Y. H. Ling, Megan E. McBee, Barnaby E. Young, Hadley D. Sikes, Peter R. Preiser. Rapid Evaluation of Vaccine Booster Effectiveness against SARS-CoV-2 VariantsMicrobiology Spectrum, 2022; DOI: 10.1128/spectrum.02257-22

Study illuminates precancerous 'clonal outgrowth' in blood cells

 A common, spontaneous mutation in blood stem cells, which has been linked to higher risks of blood cancer and cardiovascular disease, may promote these diseases by altering the stem cells' programming of gene activity and the mix of blood cells they produce, according to a study co-led by investigators at Weill Cornell Medicine, NewYork-Presbyterian, the New York Genome Center, Harvard Medical School and Dana-Farber Cancer Institute.

The blood stem cell mutation, known as DNMT3A R882leads to the growth of a large population, or "clonal outgrowth," of circulating blood cells that also contain this mutation. In general, such mutant outgrowths become increasingly common with age, and are thought to represent a very early, pre-malignant stage of cancer development. However, the molecular details of how they arise have been hard to pin down, because the mutant cells broadly look and function the same as normal cells. In the study, which appears Sept. 22 in Nature Genetics, the researchers surmounted this challenge to illuminate the effects of R882 mutations in DNMT3A, the most commonly mutated gene in blood cells.

"These findings help us understand how these mutated cells outgrow normal cells, and pave the way for possible future interventions targeting these cells to prevent cancers and other clonal outgrowth-related conditions," said study senior author Dr. Dan Landau, associate professor of medicine in the Division of Hematology and Medical Oncology, associate professor of physiology and biophysics and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, a core faculty member of the New York Genome Center and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.

The study was a collaboration between Dr. Landau's laboratory and the laboratory of Dr. Irene Ghobrial, professor of medicine at Harvard Medical School and the Dana Farber Cancer Institute. Dr. Ghobrial's team supplied samples of blood stem cells from the marrow of patients in remission from multiple myeloma -- patients in which, they have found, blood cell clonal outgrowths are relatively common.

Dr. Landau's team evaluated more than 6,000 cells from the patients, using "single-cell multi-omics" techniques to detect the DNMT3A R882 mutationand to map gene activity and chemical marks on DNA called methylations, programming marks that switch off nearby genes. In this way, they recorded in unprecedented detail how the mutation-containing blood stem cells differed from their normal counterparts.

The researchers found, for example, that the mutant stem cells' production of mature blood cells was skewed towards red blood cells and the cells that make blood-clotting platelets -- providing potential rationales underlying the higher risk of cardiovascular disease in patients with clonal outgrowths in their blood.

The gene DNMT3A normally encodes an enzyme called a methyltransferase, which helps place methylations on DNA. The researchers found that the mutation's disruption of normal methylation led to a lack of these "off switches" across the genome and the abnormal activation of key genes. The latter included inflammation-driving genes and cancer-associated growth genes -- all consistent with a growth and survival advantage for the mutant cells, and a higher risk of their progression to cancer.

"Our hope is that by uncovering molecular signatures like these we'll be able to target these clonal outgrowths and prevent cancer development in people who are still healthy," said study co-first-author Dr. Anna Nam, assistant professor of pathology and laboratory medicine in the Department of Pathology and Laboratory Medicine and a member of the Meyer Cancer Center at Weill Cornell Medicine, and a pathologist at NewYork-Presbyterian/Weill Cornell Medical Center.

The researchers plan to do further studies of clonal outgrowths resulting from other mutations. They are also developing their multi-omics techniques to increase the speed and scale of these studies.

"We should soon be able to do studies of many more cells at a time, giving us a more complete picture of what is going on," said co-first author Neville Dusaj, a Tri-institutional MD-PhD Program student in the Landau laboratory.

Story Source:

Materials provided by Weill Cornell MedicineNote: Content may be edited for style and length.

Journal Reference:

  1. Anna S. Nam, Neville Dusaj, Franco Izzo, Rekha Murali, Robert M. Myers, Tarek H. Mouhieddine, Jesus Sotelo, Salima Benbarche, Michael Waarts, Federico Gaiti, Sabrin Tahri, Ross Levine, Omar Abdel-Wahab, Lucy A. Godley, Ronan Chaligne, Irene Ghobrial, Dan A. Landau. Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylationNature Genetics, 2022; DOI: 10.1038/s41588-022-01179-9

Most long COVID patients recover: study

 A McMaster University-led study has found that most people infected with the SARS-CoV2 virus recover within 12 months, irrespective of the severity.

However, although 75 per cent had recovered at the 12-month mark after becoming ill with the virus, 25 per cent of patients still had at least one of the three most common symptoms, including coughing, fatigue and breathlessness. Researchers also found that patients with persistent symptoms also had antibodies associated with autoimmune illnesses, as well as raised levels of cytokines, which cause inflammation.

Researchers gleaned the results by surveying 106 people recovering from COVID-19 infections at three, six and 12 months after contracting the disease. All patients surveyed were otherwise healthy and had no pre-existing autoimmune conditions or any other underlying diseases pre-pandemic.

"Generally, one should not worry if they are feeling unwell right after their infection, as the chances of recovering within 12 months is very high, and just because you have typical long COVID symptoms at three months does not mean they will stay forever," said senior author Manali Mukherjee, an assistant professor of the Department of Medicine.

"However, the study highlights that at 12 months, if you still feel unwell and the symptoms are persisting or worsening, you should definitely seek medical attention."

Mukherjee said patients with persistent long COVID symptoms should see a rheumatologist, as they specialize in autoimmune disorders and can better assess development of rheumatological complications and the need for an early intervention.

She said that most patients with long COVID are currently assessed by respirologists or infectious disease specialists, who do not specialize in autoimmunity.

Mukherjee said that of the patients who recovered, a reduction in autoantibodies and cytokines was matched by their symptoms improving. Those who had elevated antibody and cytokine levels after one year were those whose symptoms persisted.

"Sometimes, while the body is fighting the virus, the immune system gets so amped up that, in addition to making antibodies that kill the virus, it can produce those that attack the host," said Mukherjee.

"However, the general tendency of the body after it fights a severe virus like SARS-COV2, is to recover, and its often paced out varying from individual to individual."

Mukherjee is leading the upcoming COVID-19 Immunity Task Force-funded 'Autoimmunity in Post-Acute COVID Syndrome' study and is Hamilton site lead for the Canadian Respiratory Research Network-Long COVID study, both of which are currently recruiting for participants.

Mukherjee led her study in collaboration with researchers from the University of British Columbia.

Parts of the study were funded by grants from Cyclomedica (Canada), Weston Foundation, Michael Smith Foundation for Health Research, UBC Strategic Initiative Fund and COVID-19 Immunity Task Force.

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Materials provided by McMaster UniversityNote: Content may be edited for style and length.

Journal Reference:

  1. Kiho Son, Rameen Jamil, Abhiroop Chowdhury, Manan Mukherjee, Carmen Venegas, Kate Miyasaki, Kayla Zhang, Zil Patel, Brittany Salter, Agnes Che Yan Yuen, Kevin Soon-Keen Lau, Braeden Cowbrough, Katherine Radford, Chynna Huang, Melanie Kjarsgaard, Anna Dvorkin-Gheva, James Smith, Quan-Zhen Li, Susan Waserman, Christopher J Ryerson, Parameswaran Nair, Terence Ho, Narayanaswamy Balakrishnan, Ishac Nazy, Dawn ME Bowdish, Sarah Svenningsen, Chris Carlsten, Manali Mukherjee. Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long-COVID symptomsEuropean Respiratory Journal, 2022; 2200970 DOI: 10.1183/13993003.00970-2022