Stanford University Medicine Study: SARS-CoV-2 infection f

Does SARS-CoV-2 hide in fat cells?

Study by Stanford Medicine Researchers have shown that SARS-CoV-2 can infect human adipose tissue. This phenomenon has been seen in laboratory experiments performed on adipose tissue removed from patients who underwent bariatric and cardiac surgeries and subsequently infected in a laboratory dish with SARS-CoV-2. This was also confirmed in autopsy samples from deceased COVID-19 patients.

Obesity is a consistent and independent risk factor for SARS-CoV-2 infection as well as for the progression of patients, once infected, to severe illness and death. The reasons given for this increased weakness range from impaired breathing caused by the stress of being overweight, to an altered immune response in obese people.

But the new study offers a more direct cause: SARS-CoV-2, the virus that causes COVID-19, can directly infect adipose tissue (which most of us refer to as just “fat”). This, in turn, sets off a cycle of viral replication within the resident fat cells, or adipocytes, and causes apparent inflammation in the immune cells that hang in the fat tissue. Inflammation turns even uninfected “bystander” cells within tissues into an inflammatory state.

“With 2 in 3 American adults being overweight and more than 4 in 10 obese, this is a potential cause for concern,” Tracy McLaughlinMD, professor of endocrinology.

The results are described in a study published online on September 22 Translational Medicine Sciences. McLaughlin and Catherine Bleach, MD, PhD, professor of infectious diseases, are senior authors of the study. Lead authorship is shared by former postdoctoral scholar Giovanni Martinez Colon, Ph.D., Postgraduate student Kalani Ratnasiri.

The COVID-19 fat connection

Obesity is medically defined as having a body mass index (weight in kilograms divided by the square of height in metres) of 30 or more. A person with a BMI of 25 or more is defined as being overweight. McLaughlin said that individuals who are obese are ten times more likely to die from COVID-19, but the increased risk of poor outcomes from SARS-CoV-2 infection begins at a BMI of 24.

“The sensitivity of adipose tissue to SARS-CoV-2 infection may play a role in making obesity a risk factor for COVID-19,” said Bleach, M.D., George E. and Lucy Becker Professor of Medicine. Delicately injured adipose tissue pumps out the inflammatory chemicals you see in the blood of severe Covid patients. It is reasonable to conclude that having a lot of affected fat could contribute to the overall inflammatory profile of critically ill COVID-19 patients.”

The scientists obtained samples of fatty tissue from various locations in the bodies of 22 patients undergoing bariatric or heart surgery at Stanford Medicine’s Bariatric and Cardiac Surgery Clinic. Then, in a secure facility, the researchers infected the samples with a solution containing SARS-CoV-2 or, as a control, a solution free of SARS-CoV-2. Rigorous experiments have shown that the virus can infect and multiply in and out of fat cells and cause new infections in other cells.

Adipose tissue contains not only fat cells, but also a variety of immune cells, including a type called macrophages. These cells (whose name derives from two Greek words meaning “big eaters”) perform a number of actions that range from tissue repair and general trash cleaning to ferocious attacks on perceived pathogens—sometimes causing significant collateral damage to normal tissues in the process.

The researchers identified a subset of macrophages in adipose tissue that was infected with SARS-CoV-2, although it is transient. SARS-CoV-2 infection of these macrophages is abortive: they do not produce viable viral progeny. But it does induce a significant mood change in macrophages.

Once infected, these macrophages not only inflame themselves, but also secrete substances that call on more inflammatory immune cells, as well as inducing inflammation in ‘adjacent uninfected bystander cells,’ said Bleich.

Adipose tissue surrounds the heart, intestines, kidneys, and pancreas, which can be negatively affected by tissue inflammation. Unfortunately, the scientists found that the infection was able to cause inflammation in every SARS-CoV-2-infected fat tissue sample they collected and analyzed.

The genetic material encoding SARS-CoV-2 was almost always present in the adipose tissue of the various body regions of eight patients who died from COVID-19. After examining the tissues of two other patients who had died of COVID-19, the team saw infiltration of inflammatory immune cells adjacent to the affected fat cells in the epicardial fat.

“This was a major concern for us, as the epicardial fat is located next to the heart muscle, and there is no physical barrier separating it,” McLaughlin said. Therefore, any inflammation there may directly affect the heart muscle or the coronary arteries.

ACE2 is missing

Oddly enough, ACE2 – the cell surface molecule implicated as the primary SARS-CoV-2 receptor – appears to play little or no role in the virus’s ability to infect fat cells.

The manner in which SARS-CoV-2 gains entry into fat cells and connectives in adipose tissue remains a mystery. The primary mode of entry occurs when the virus binds to a protein called ACE2 that is found on cell surfaces in many tissues of the body. Although ACE2 performs important, legitimate functions, the virus does not care what ACE2 does for a living – it considers this cell-surface protein merely a docking station.

That was the height of the irony for McLaughlin and Bleach, who started the study because they saw reports suggesting, although unproven, that ACE2 may be present in fat tissue. (No one claimed to have seen the protein itself, Bleach added.)

But the researchers found, to their surprise, that the ACE2 enzyme was virtually absent from cells in fat tissue.

“It is very unlikely that the virus entered via ACE2, because we were unable to detect the functional protein in adipose tissue,” Bleach said.

This means that removing SARS-CoV-2 from fat tissue may require new drugs. Licensed monoclonal antibody therapies for COVID-19, for example, generally work by interfering with the ACE2/SARS-CoV-2 interaction.

The ability of adipose tissue to act as a reservoir where SARS-CoV-2 can hide also raises the possibility that it may contribute to persistent post-infectious symptoms collectively called prolonged COVID, a hypothesis that McLaughlin and Blech have begun to explore.

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

The study was funded by the National Institutes of Health (grants R21AI159024, 5T32 AI007502, and T32 DK007217), the American Diabetes Association, the Stanford University Innovative Drug Accelerator, the Botnar Research Center for Child Health, the Swiss National Science Foundation, the Chan Zuckerberg Biohub Foundation, the National Science Foundation, and the Bill and Melinda Foundation Gates.

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