Stanford Medicine study shows SARS-CoV-2 can infect human fatty tissue

Stanford Medicine study shows SARS-CoV-2 can infect human fatty tissue

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

A study by Stanford Medicine researchers shows that SARS-CoV-2 can infect human fatty tissue. This phenomenon has been observed in laboratory experiments carried out on adipose tissue excised from patients undergoing bariatric and cardiac surgeries, and then infected in a laboratory dish with SARS-CoV-2. It has further been confirmed in autopsy samples from deceased COVID-19 patients.

Obesity is an established 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 vulnerability range from impaired breathing resulting from the pressure of extra weight to an impaired immune response in obese people.

But the new study provides a more direct reason: SARS-CoV-2, the virus that causes COVID-19, can directly infect adipose tissue (which most of us simply call “fat”). This, in turn, sets up a round of viral replication in the resident fat cells, or adipocytes, and causes pronounced inflammation in the immune cells that hang around in the fatty tissues. Inflammation converts even uninfected “spectator” cells in the tissue into an inflammatory state.

With 2 in 3 American adults overweight and more than 4 in 10 obese, this is a potential cause for concern.”

Tracey McLaughlin, MD, professor of endocrinology

The results are described in a study published online September 22 in Science Translational Medicine. McLaughlin and Catherine Blish, MD, PhD, professor of infectious diseases, are the study’s lead authors. Primary authorship is shared by former postdoctoral researcher Giovanny Martínez-Colón, PhD, and graduate student Kalani Ratnasiri.

The fat-COVID-19 connection

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

“Adipose tissue susceptibility to SARS-CoV-2 infection may play a role in turning obesity into a risk factor for COVID-19,” said Blish, who is George E. .and Lucy Becker. “Infected fatty tissue pumps out precisely the inflammatory chemicals that you see in the blood of patients with severe COVID. It is reasonable to infer that having a lot of infected fat could contribute to the overall inflammatory profile of critically ill patients with COVID-19.

The scientists obtained samples of fatty tissue from various locations in the bodies of 22 patients undergoing bariatric or cardiothoracic surgery at Stanford Medicine’s Bariatric 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 solution without SARS-CoV-2. Rigorous experiments showed that the virus could infect and replicate in fat cells, break out of cells, and cause new infections in other cells.

Adipose tissue not only contains 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 cleaning up of garbage, to ferocious attacks on perceived pathogens -; sometimes producing substantial collateral damage to normal tissue in the process.

Researchers have identified a subset of macrophages in fatty tissue that are infected with SARS-CoV-2, albeit transiently. SARS-CoV-2 infection of these macrophages is abortive: it produces no viable viral progeny. But it induces a major mood shift in macrophages.

“Once infected, these macrophages not only inflame themselves, but also secrete substances that call for more inflammatory immune cells, in addition to inducing inflammation in neighboring uninfected ‘control cells’,” Blish said. .

Fat tissue surrounds our heart, intestines, kidneys, and pancreas, which can be affected by tissue inflammation. Worryingly, scientists found an infection capable of causing inflammation in virtually every SARS-CoV-2-infected fatty tissue sample they collected and analyzed.

Genetic material coding for SARS-CoV-2 was almost invariably present in fatty tissue from various body regions of eight patients who died of COVID-19. Examining tissue from two other patients who died of COVID-19, the team found infiltration of inflammatory immune cells adjacent to infected fat cells in the epicardial fat.

“We were very concerned about this because epicardial fat sits right next to heart muscle, with no physical barrier separating them,” McLaughlin said. “So any inflammation can directly affect the heart muscle or the coronary arteries.”

ACE2 missing

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

The method by which SARS-CoV-2 enters fat cells and macrophages in fatty tissue remains mysterious. The established primary mode of entry occurs when the virus binds to a protein called ACE2 which is found on the surface of cells in many body tissues. Although ACE2 performs important and legitimate functions, the virus does not care what ACE2 does in life -; he sees this cell surface protein as a mere docking station.

This was the height of irony for McLaughlin and Blish, who initiated the study because they had seen reports suggesting, though not proving, that ACE2 might be present in fatty tissue. (No one had claimed to have seen the protein itself, Blish added.)

But the researchers found, to their surprise, that ACE2 was virtually non-existent on cells found in fatty tissue.

“It’s very unlikely that the virus enters through ACE2, because we couldn’t detect the functional protein in adipose tissue,” Blish said.

This means that clearing SARS-CoV-2 from fatty tissue could require new drugs. Monoclonal antibody therapies licensed for COVID-19, for example, typically work by interfering with the ACE2/SARS-CoV-2 interaction.

The potential of adipose tissue to serve as a reservoir where SARS-CoV-2 can hide also raises the possibility that it may contribute to persistent post-infectious symptoms collectively known as long COVIDs, 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 Baselland Cantonal Hospital in Liestal, Switzerland, contributed to the work.

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

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