Experiments conducted at the State University of Campinas (Unicamp) confirm that the new coronavirus (SARS-CoV-2) may be capable of infecting human fat cells and remaining inside them. This data can help understand why obese individuals are at greater risk of developing the severe form of Covid-19.
In addition to being more affected by chronic diseases, such as diabetes, dyslipidemia and hypertension – which in themselves are risk factors –, obese people would, according to the hypothesis investigated at Unicamp, have a greater reservoir for the virus in their body.
“We have fat cells spread throughout the body and obese people have them in even greater quantity and size. Our hypothesis is that adipose tissue would serve as a reservoir for SARS-CoV-2. With more and larger adipocytes, obese people would tend to have a higher viral load. However, we still need to confirm whether, after replication, the virus can leave the viable fat cell to infect other cells”, Marcelo Mori, professor at the Institute of Biology (IB) and coordinator of the investigation, explains to Agência Fapesp.
The experiments with human adipocytes are being conducted in vitro, with support from Fapesp, at the Laboratory for Studies of Emerging Viruses (Leve). The unit has biosafety level 3, one of the highest, and is managed by José Luiz Proença Módena, IB professor and coordinator, alongside Mori, of the task force created by Unicamp to face the pandemic (read more). The results are still preliminary and have not been published.
As Mori explains, it is not in any type of human cell that SARS-Cov-2 can enter and replicate efficiently. Some favorable conditions must be present, including a membrane protein called ACE-2 (angiotensin-converting enzyme 2) to which the virus connects to invade the cell.
In comparisons made in vitro, Unicamp researchers observed that the new coronavirus infects adipocytes better than, for example, intestinal or lung epithelial cells.
And the “domination” of the fat cell by the virus becomes even more favorable when the cellular aging process is accelerated with the use of ultraviolet radiation. When measuring viral load 24 hours after this procedure, researchers observed that aged fat cells had a viral load three times higher than “young” cells.
“We use UV radiation to induce a phenomenon known as senescence in the adipocyte, which occurs naturally with aging. When cells enter senescence, they express molecules that recruit immune system cells to the site. It is an important mechanism to protect the body from tumors, for example”, explains Mori.
The problem, according to the researcher, is that in obese individuals, the elderly and those with chronic diseases, senescent cells begin to accumulate in adipose tissue, making it dysfunctional. This fact can result in the development or worsening of metabolic disorders.
Also according to Mori, the accelerated aging of the adipocyte induced by UV radiation mimics what usually occurs in the adipose tissue of obese individuals and the elderly.
“Recently, some compounds capable of killing senescent cells began to be tested in humans: they are called senolytic drugs. In animal experiments, these compounds were shown to be capable of extending lifespan and reducing the development of chronic diseases associated with aging,” says Mori.
The Unicamp group then had the idea of testing the effect of some senolytic drugs in the context of SARS-CoV-2 infection. In experiments carried out with human intestinal epithelial cells, it was observed that the treatment reduced the viral load of cells subjected to UV radiation.
“Some compounds even inhibited the presence of the virus by 95%. Now we intend to repeat the experiment using adipocytes”, says Mori.
To date, adipocytes differentiated in vitro from a type of mesenchymal stem cell (pre-adipocyte) isolated from uninfected patients undergoing bariatric surgery have been used in tests. After differentiation, the cells were exposed to a strain of the new coronavirus isolated from Brazilian patients and cultivated in the laboratory by researchers from the Institute of Biomedical Sciences at the University of São Paulo.
The next steps of the research include the analysis of adipocytes obtained directly from patients with a confirmed diagnosis of COVID-19, obtained through biopsy. “One of the objectives is to assess whether these cells are in fact infected by SARS-CoV-2 and whether the virus is replicating inside them.
Proteomic analyzes will also be conducted to discover whether SARS-CoV-2 infection affects the functioning of the adipocyte and whether it leaves any long-term sequelae in the cell. This stage of the research will be carried out in collaboration with IB-Unicamp professor Daniel Martins de Souza.
“The idea is to compare all the proteins that are expressed in cells with and without the virus. In this way, we were able to identify the signaling pathways that are altered by the infection and how this impacts cellular functioning”, explains Mori.
Premature aging
At the Department of Biochemistry and Tissue Biology at IB-Unicamp, Mori has dedicated himself in recent years to studying the biology of aging. In his current project, the researcher investigates why elderly people and people with diseases associated with aging are more susceptible to complications from COVID-19.
“This finding that senescent adipocytes have a higher viral load points to a possible link between metabolic diseases, aging and greater severity of COVID-19”, assesses the researcher.
However, it is not yet known whether the viral load is higher in these cells because they become more easily infectable when exposed to SARS-CoV-2 in culture or whether the amount of virus that enters is the same but the pathogen is able to escape. replicate more. “We need to carry out new experiments and monitor the evolution of the viral load over time”, explains Mori.
If it is confirmed that the virus causes some type of metabolic impact on the adipocyte, says Mori, the implications could be great. “Fat cells play a very important role in regulating metabolism and communication between various tissues. They signal to the brain when we should stop eating, they signal to the muscle when it is necessary to capture the glucose present in the blood and they act as a metabolic thermostat, telling us when there is a need to spend or store energy. It may be that the virus interferes with these processes, but for now this is just speculation”, says the researcher.
These aspects are being investigated in partnership with researcher Luiz Osório Silveira Leiria, professor at the Faculty of Medicine of Ribeirão Peto (FMRP-USP). Leiria coordinates a project – supported by Fapesp – which aims to discover the role of certain lipids in controlling inflammation caused in the body by SARS-CoV-2.
“The research also has a wide network of collaborators who are part of the Unicamp Task Force Against COVID-19”, highlights Mori.
Published article originally on the Agência Fapesp website.
