Novel receptors for SARS-CoV-2 and their age-dependent expression

 A study led by Mount Sinai researchers Dr. Bin Zhang, the Willard T.C. Johnson Research Professor of Neurogenetics, and Dr. Christian Forst, an Associate Professor in the Department of Genetics and Genomic Sciences, has identified potential novel receptors for SARS-CoV-2 and unveiled their tissue-specific and age-dependent expression. The findings were published on March 23 in the Federation of European Biochemical Societies Letters (FEBS Letters).

The study's multiscale network analysis suggests that SARS-CoV-2 utilizes multiple novel receptors, such as the TYOBP receptor CD300e, to facilitate its life cycle and trigger a unique response in the host system. This receptor activates IL-2 pro-inflammatory cytokine signaling, which is believed to contribute to the severity of COVID-19. Researchers identified a strong correlation between tissue age-dependency and SARS-CoV-2 infection-induced receptor expression in subcutaneous fat, tibial artery, brain substantia nigra, esophagus gastroesophageal junction, and liver.

These findings reveal that SARS-CoV-2 may exploit different receptors and pathways across various tissues and age groups, with older adults being more susceptible to severe outcomes. The study's results also provide valuable information about the host response to the virus, the hijacking of key cellular processes, and the age-dependence of these receptors in different tissues.

"These findings provide crucial insights into the gene regulatory organization during SARS-CoV-2 infection and the tissue-specific, age-dependent expression of cell receptors involved in COVID-19," said Dr. Bin Zhang. "This information is critical for public health as it allows us to better understand the molecular mechanisms of SARS-CoV-2 infection and develop new therapeutic interventions against COVID-19."

The study highlights the importance of understanding the host response to viral infections and how age can impact the severity of the disease. With these new insights, researchers can develop targeted therapies and interventions to mitigate the impacts of COVID-19 on vulnerable populations, such as older adults and individuals with pre-existing conditions.

The methods employed in this study involved a multiscale network analysis utilizing bulk and single-cell omics data, which allowed the researchers to analyze the complex biological systems of SARS-CoV-2 infection. They integrated large-scale transcriptomic datasets from COVID-19 patients and healthy individuals, along with protein-protein interaction (PPI) data and protein expression data, to construct a comprehensive host-virus interactome.

This approach enabled them to identify key genes, proteins, and molecular pathways involved in SARS-CoV-2 infection and the host response, and the age-dependent expression patterns of novel receptors. The research team also validated the findings using a combination of in vitro and in vivo experiments, further substantiating the potential roles of the newly discovered receptors in SARS-CoV-2 infection and COVID-19 severity.

Dr. Christian Forst added, "The discovery of novel receptors that SARS-CoV-2 utilizes, and their age-dependent expression, offers new avenues for research and potential therapeutic strategies. This could be especially significant for older adults who have a higher risk of severe COVID-19 outcomes. Our research will help guide public health strategies and support targeted therapies for vulnerable populations."

More information: Christian V. Forst et al, Multiscale network analysis identifies potential receptors for SARS‐CoV ‐2 and reveals their tissue‐specific and age‐dependent expression, FEBS Letters (2023). DOI: 10.1002/1873-3468.14613

https://medicalxpress.com/news/2023-04-receptors-sars-cov-age-dependent.html

Dietary supplement helps combat resistance in breast cancer

 Many cancer therapies do not produce the hoped-for results. A common reason for this is that the tumors develop resistance to the medications. This is the case, for example, with alpelisib, a drug that has been approved for use in Switzerland for the past few years as a treatment for advanced breast cancer.

A research group at the Department of Biomedicine of the University of Basel has now discovered that the loss of the neurofibromin 1 (NF1) gene leads to a reduced response to alpelisib. The researchers also found that the dietary supplement N-acetylcysteine restores the sensitivity of cancer cells to this treatment. The findings have been published in the journal Cell Reports Medicine on April 11.

Loss of gene triggers resistance

At the moment, patients with advanced and metastatic breast cancer lack effective treatment options. The PI3K signaling pathway is often overactive in breast cancer due to mutations promoting tumor development. The approval of the PI3K inhibitor Alpelisib was therefore keenly anticipated.

"Unfortunately, it turned out that the success of the medication is severely limited by resistance," says Professor Mohamed Bentires-Alj, head of the research group. "Hence, we urgently need to find out more about how resistance arises."

So his team went looking for the genetic basis of the resistance—in other words, trying to find out which genes had changed to turn cancer cells resistant. They found that mutations that switched off production of the NF1 protein made the tumors resistant to treatment with alpelisib. It is known that NF1 suppresses the growth of tumors through a variety of signaling pathways, but the gene had not yet been linked to resistance to alpelisib.

Further experiments run by the researchers confirmed that the loss of NF1 also leads to resistance in human cancer cells and in tissue cultured from tumors. "So the absence of NF1 is the elephant in the room; it throws everything into disarray within the cell and hinders successful treatment," says Bentires-Alj.

A promising pairing with an expectorant

An analysis shows that the loss of NF1 affects the cell's energy reserves: "They stop producing as much energy using mitochondria; instead, they switch to other energy production pathways," says the lead author of the study, Dr. Priska Auf der Maur.

Given these changes, the researchers conducted experiments with the known antioxidant N-acetylcysteine, which has a similar effect on energy metabolism and therefore was expected to emulate the effects of NF1 loss. This substance is a well-known dietary supplement, as well as an ingredient in many cough medicines.

Surprisingly, N-acetylcysteine had the opposite effect: it restored the effectiveness of alpelisib in resistant cancer cells. In fact, it increased it. This occurs via an additional intervention in another signaling pathway that also plays an important role in tumor growth, as the researchers discovered through further analysis. Interestingly, the loss of NF1 also plays a role in resistance to other medications. A combination therapy with N-acetylcysteine could also be a possibility in these cases.

"As N-acetylcysteine is a safe and widespread additive, this result is highly relevant for clinical research," says Bentires-Alj. He thinks that a combination of N-acetylcysteine with alpelisib could improve the treatment of advanced breast cancer. The next step would now be to run clinical studies with breast cancer patients to confirm the positive effects observed in the lab.

More information: Rogier W Bentires-Alj, N-acetylcysteine overcomes NF1-loss-driven resistance to PI3K alpha inhibition in breast cancer, Cell Reports Medicine (2023). DOI: 10.1016/j.xcrm.2023.101002. www.cell.com/cell-reports-medi … 2666-3791(23)00112-X

https://medicalxpress.com/news/2023-04-dietary-supplement-combat-resistance-breast.html

How COVID variants escape immune system 'killers'

 Omicron subvariants of SARS-CoV-2—the virus behind COVID-19—have shown an uncanny knack for evading antibodies produced either by vaccines or exposure to earlier versions of the virus, leading to many breakthrough infections. However, in order to sicken people, these viral variants must also avoid "killer" T cells, immune cells that are unleashed when the immune system detects foreign pathogens.

A new Yale study published April 10 in the Proceedings of the National Academy of Sciences reveals new insights into how these omicron variants are able to avoid destruction by these T cells.

For the study, a team led by Miyu Moriyama, a postdoctoral fellow at Yale School of Medicine, measured activity of MHC (major histocompatibility complex) molecules that present fragments of viruses for recognition by appropriate T cells. These MHC molecules alert the T cells of foreign pathogens that then become targets for the T cells.

The researchers found that the activity of these MHC molecules was substantially lower in cells exposed to five omicron subvariants of SARS-CoV-2 as well as earlier versions of the virus, according to Moriyama, who is part of the lab of Akiko Iwasaki, Sterling Professor of Immunobiology.

But the omicron variants, the researchers found, were particularly adept at shutting down the activity of MHC compared with earlier versions of the COVID-19 virus. Meanwhile, cells infected by a flu virus were found to have much greater MHC activity.

Reduced activity in these MHC molecules, researchers say, may make T cells less likely to locate COVID viral targets.

"The findings will help guide researchers as they investigate possible ways to overcome MHC suppression by viral infections and may help in the development of vaccines that mobilize T cells as well as antibody response against viruses," Moriyama said.

More information: Miyu Moriyama et al, Enhanced inhibition of MHC-I expression by SARS-CoV-2 Omicron subvariants, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2221652120

https://medicalxpress.com/news/2023-04-insights-covid-variants-immune-killers.html

Probiotic company finds links between youthful gut microbiota and potential centenarians

 With a growing body of scientific evidence illustrating the influence of gut microbiota on human health, researchers from AIage Life Science, a probiotics manufacturer in China, investigated the microflora inhabiting the guts of the world's healthiest people—centenarians.

In the paper, "Longevity of centenarians is reflected by the gut microbiome with youth-associated signatures," published in Nature Aging, the researchers studied the microbiomes of 1,575 individuals aged 20 up to 117, with 297 of them reported to be 100 years old or older. A Research Briefing on the study, titled "Youth-associated signatures in the gut microbiome of centenarians," has been published in the same journal issue.

Participants were evaluated in five age-related groups. Young adults (n = 314, 20–44 years), a middle-aged group (n = 277, 45–65 years), old adults (n = 386, 66–85 years), a nonagenarian group (n = 301, 90–99 years), and a centenarian cohort (n = 297, 100–117 years).

The researchers discovered that the gut microbiome signature in centenarians resembles that of young adults with an overrepresentation of Bacteroides spp., an increase in species evenness (species have a similar abundance), an enrichment of potentially beneficial species from the Bacteroidetes phylum and depletion of potential pathobionts (harmless but can become pathogenic under certain circumstances).

A smaller group of 45 centenarians was tested twice over a year and a half. Results from the group indicated that as centenarians age, the signature species evenness and low pathobionts continued to develop and were enhanced or conserved.

The researchers propose that this microbiome signature is associated with longevity, as they observed in their study, and state that this may counteract the senescence or chronic diseases that generally accompany aging, which this study could not have observed.

The researchers are currently isolating thousands of bacteria strains from the centenarians and testing their benefits on animal models in search of microorganisms that are able to extend the human lifespan. This future research should be incredibly useful to AIage Life Science, the company the researchers work for, as it already sells a probiotic product that claims to do just that.

How old?

A quick side note to anyone wondering if the oldest living person on the planet took part in this study (up to 117): It is unclear and remarkably unstated anywhere in the paper whether there is a participant who claims to be 117 years old, or if this is an arbitrary range on the part of the researchers. The way it is written implies the former and so must be explored briefly as it highlights a potential issue with interpreting the study.

The ages of the participants were derived by participant self-reporting (at some point in their lives) as birth records did not exist in Guangxi province before 1949. This places anyone over age 72 at the time of the study into the category of having an unverifiable age.

Unlike the West, there is no emphasis on staying young in Chinese culture, quite the opposite. It is possible that in a society where elders hold high status, some might seek to exaggerate when asked about their age. That or we can believe, without evidence, that the world's oldest living person wandered into a study on aging completely unnoticed.

According to the researchers, "All participants were community-dwelling and permanently lived in Guangxi province, China." The community is renowned for the high number of centenarians in the population. This is notably the same community that produced Luo Meizhen, a previous claimant to the world record for the oldest person ever to have lived, reaching the age of 127. Chinese authorities somehow confirmed her age, but it could not be verified otherwise because, again, no birth records existed in Guangxi province previous to 1949. There was also a potential math problem as she would have been 61 when giving birth to her son, which would have also made her the oldest person to have given birth at the time.

There are plenty of places in the world with people over the age of 100 that have verifiable birth records where this study could be repeated. Guangxi province in China will not be on that list for centenarians for at least another 26 years.

More information: Shifu Pang et al, Longevity of centenarians is reflected by the gut microbiome with youth-associated signatures, Nature Aging (2023). DOI: 10.1038/s43587-023-00389-y

Youth-associated signatures in the gut microbiome of centenarians, Nature Aging (2023). DOI: 10.1038/s43587-023-00395-0

https://medicalxpress.com/news/2023-04-probiotic-company-links-youthful-gut.html

New approach targets norovirus, world's leading cause of foodborne infection

 Every year, norovirus causes hundreds of millions of cases of food poisoning—and the deaths of at least 50,000 children—yet there exists no real way to control it. The virus has proven exceptionally difficult to study in the lab, and scientists have struggled to develop effective vaccines and drugs.

A new study at Washington University School of Medicine in St. Louis describes a creative way to make a vaccine against norovirus by piggybacking on the highly effective vaccines for rotavirus, an unrelated virus that also causes diarrhea.

The researchers created an experimental rotavirus-norovirus combo vaccine by adding a key protein from norovirus to a harmless strain of rotavirus. Mice that received the experimental vaccine produced neutralizing antibodies against both rotavirus and norovirus. The study, available online in Proceedings of the National Academy of Sciences, outlines an innovative approach to preventing one of the most common and intractable viral infections.

"Pretty much everyone has had norovirus at some point," said senior author Siyuan Ding, Ph.D., an assistant professor of molecular microbiology. "You go out to eat, and the next thing you know you're vomiting and having diarrhea. You will recover, but it's going to be a rough three days or so. For kids in the developing world who don't have access to clean water, though, it can be deadly. The rotavirus vaccines work really well, and there are already global distribution systems set up for them, so based on that, we saw an opportunity to finally make some headway against norovirus."

Before the first rotavirus vaccines were rolled out in 2006, half a million children around the world died every year of diarrhea caused by rotavirus infection. Now, the number is estimated to be about 200,000—still high but a huge improvement. Four rotavirus vaccines are in use around the world. All are live-virus vaccines, meaning they are based on weakened forms of rotavirus capable of triggering an immune response but not of making people sick.

Human norovirus, on the other hand, has stymied scientific investigation for decades. It doesn't infect mice or rats or any other ordinary lab animals, so the kinds of experiments that led to the development of rotavirus vaccines have been impossible to replicate with norovirus.

Ding and colleagues—including first author Takahiro Kawagishi, Ph.D., a staff scientist in Ding's lab, and co-corresponding author Harry B. Greenberg, MD, a professor emeritus of medicine at Stanford University—came up with the idea of using rotavirus to bypass the technical difficulties of working with norovirus. They worked with a laboratory strain of rotavirus as a stand-in for one of the approved rotavirus vaccines, which are proprietary.

The researchers inserted the gene for the protein that forms the outer surface of human norovirus into the genome of the rotavirus lab strain. Then, they administered the modified rotavirus to immunocompromised infant mice by mouth, the same way rotavirus vaccines are given to children. They took blood and fecal samples four, six and eight weeks later. Nine weeks after the initial immunization, the researchers gave the mice a booster by injection and took samples again a week later.

A strong antibody response was evident in the blood of nine of 11 mice tested, and in the intestines of all 11 mice. Even better, some of the antibodies from the blood and the intestines were able to neutralize both viruses in human "mini-gut" cultures in a dish. Such cultures, also known as organoids, are grown from human stem cells and replicate the surface of the human gut.

"Traditionally, vaccine studies have focused on the antibody response in the blood, because we understand that part of the immune response the best," Ding said. "But norovirus and rotavirus are gut viruses, so antibodies in the blood are less important than the ones in the intestines in terms of fighting off these viruses. The fact that we saw a strong antibody response in the intestines is a good sign."

The next step is to show that animals immunized with the experimental vaccine are less likely to get sick or die from norovirus. Ding has such experiments underway.

The power of this study is that it outlines a novel approach that could accelerate vaccine development for a variety of troublesome organisms that cause diarrhea, especially in resource-limited countries where many of these infections occur.

"There are a lot of intestinal pathogens out there for which we don't have good treatments or vaccines," Ding said. "In principle, we could put a gene from any organism that infects the intestinal tract into the rotavirus vaccine to create a bivalent vaccine. We'd have to find the right targets to produce a good immune response, of course, but the principle is simple.

"As basic scientists, we rarely get the chance to actually move something forward into the clinic," Ding continued. "We study what the virus does and how the host responds at a basic level. This is a rare opportunity for our work to affect human health directly and make people's lives better."

More information: Takahiro Kawagishi et al, Mucosal and systemic neutralizing antibodies to norovirus induced in infant mice orally inoculated with recombinant rotaviruses, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2214421120

https://medicalxpress.com/news/2023-04-approach-norovirus-world-foodborne-infection.html

Doctor-Office TV Marketers Convicted in $1 Billion Fraud

• Goldman Sachs, Illinois governor invested in Outcome Health
• Company used phantom ad inventory to falsely boost revenue

 

Three former executives of Outcome Health, a company that provided advertising on TVs it installed in doctors’ offices across the US, were convicted of defrauding clients, lenders and investors of about $1 billion.

A federal jury in Chicago on Tuesday returned guilty verdicts against co-founders Rishi Shah and Shradha Agarwal, both 37, and former Chief Financial Officer Brad Purdy, 33, the US Department of Justice said in a statement. They were accused of lying to clients and taking money for ads that were never placed, and then misrepresenting the health of the company to investors. 

https://www.bloomberg.com/news/articles/2023-04-11/doctor-office-tv-marketers-convicted-in-1-billion-fraud

3rd Dem lawmaker leaves party, switches to Republican within a month

 Democrats were dealt another blow from within their own ranks this week as yet another state lawmaker declared he was leaving the party.

According to a Monday report by The Advocate, a Louisiana-based newspaper, state Rep. Jeremy LaCombe announced he had left the Democratic Party and would be registering as a Republican.

It was not immediately clear what prompted LaCombe's departure, however he is now the second Louisiana Democrat in less than a month to switch party affiliations, and the third nationwide after another state lawmaker in North Carolina did the same.

Last month, Louisiana state Rep. Francis Thompson gave Republicans in the state House a supermajority after he switched his party affiliation, and earlier this month, North Carolina state Rep. Tricia Cotham gave Republicans in the state House a supermajority with her switch as well.

Republican Louisiana state Rep. Jeremy LaCombe, a former Democrat. (Office of Rep. Jeremy LaCombe)

The switches come as President Biden faces a near-record low approval rating among key groups, including women (43% now vs. 42% low), voters ages 45+ (41% vs. 39% low), suburban voters (41% vs. 39% low), rural voters (31% vs. 30% low) and Democrats (81% vs. 78% low) – Democratic men in particular (79% vs. 78% low), according to a recent Fox News poll.

Biden is also at a low mark of 41% approval among suburban women. 

North Carolina state Rep. Tricia Cotham announces she's leaving the Democratic Party and becoming a Republican at the North Carolina GOP headquarters in Raleigh, April 5, 2023. (Screenshot/WBTV)

Additionally, a separate recent poll found that only a third of Americans believed Biden deserved to be re-elected in 2024.

https://www.foxnews.com/politics/democrats-another-blow-lawmaker-leaves-party-switches-republican