Immune system hyperactivation may cause post-COVID syndromes

Researchers at Cedars-Sinai have proposed a theory for how SARS-CoV-2, the virus that causes COVID-19, infects the body. Their hypothesis, published in Frontiers in Immunologycould explain why some people have symptoms long after the initial infection.

“We put together several pieces of data to create a bigger picture that may explain why some people’s immune systems go haywire, leading to post-acute syndromes, including childhood multisystem inflammatory syndrome (MIS-C) and long-term COVID in children and adults,” said Moshe Arditi, MD, executive vice chair of the Division of Pediatrics for Research, part of Cedars-Sinai Guerin Children’s, and senior author of the article.

MIS-C is a rare but dangerous condition in children that can occur weeks after infection with SARS-CoV-2. Long COVID-19 – often referred to as long COVID-19 – is a term used to describe a constellation of health problems that some people experience as a result of their infection with SARS-CoV-2. Symptoms can last for months or even years.

SARS-CoV-2 is thought to cling to cells via spikes located on the surface of the virus. These spike proteins are made up of molecular motifs, which are bits of amino acids that make up a protein. These small molecular motifs may have what the scientists call “superantigen” features, meaning the immune system may overreact to their presence.

The spike protein may also have neurotoxic motifs that can cross the blood-brain barrier and damage brain cells, according to the authors. This hypothesis could explain the “brain fog” and other neurological symptoms associated with COVID-19 and long-term COVID.

The hypothesis is based on several published studies on COVID-19 and other diseases caused by viruses. An example of such a study by Arditi and his longtime collaborator Ivet Bahar, PhD, was published in the Proceedings of the National Academy of Sciences in 2020. Bahar and Arditi created a computer model showing how molecular motifs on the spike protein interact with immune cells. The superantigenic molecular motifs cause the immune cells to release a plethora of infection-fighting proteins known as cytokines that fight the virus, but can also accidentally attack the body’s organs. In children, this can manifest as MIS-C.

Other studies have reported that people with long-term COVID can carry fragments of the virus in their gut or other parts of their bodies for months after initial infection. Continued exposure to motifs that lodge in different parts of the body and have superantigen-like properties may trigger autoimmune symptoms in people with long-term COVID and MIS-C, according to the authors.

“We need to do more research to prove whether this is indeed the mechanism that causes long-term COVID so that we can develop treatments to block it,” said Magali Nova Rivas, PhD, a researcher at Cedars-Sinai and lead author of the paper.

Arditi, the GUESS?/Fashion Industries Guild Chair in Community Child Health in Cedars-Sinai, who Research Center for Infectious and Immunological Diseasesand colleagues are currently conducting a study analyzing cerebrospinal fluid samples from people with long-term COVID symptoms for evidence of neurotoxic motives.

Rebecca A. Porritt, PhD, assistant professor in Cedars-Sinai’s Departments of Pediatrics and Biomedical Sciences, also contributed to this work.

Funding: The study was funded by the National Institutes of Health (prize numbers R01AI072726, R01AI072726-10S, GM103712, R01GM139297, R01HL139766, and R01HL159297), the American Heart Association (Career Development Award AHA 20CDA35260258) and the Cedars-Sinai Precision Health Award.

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