The Long COVID Puzzle: Autoimmunity, Inflammation, and Other Possible Causes – Yale Medicine

The underlying cause of Long COVID is still a puzzle to researchers. But Akiko Iwasaki, PhD, Sterling Professor of Immunobiology and Molecular, Cellular, and Developmental Biology at Yale School of Medicine (YSM) and co-lead investigator of the Yale RECOVERY and Yale LISTEN studies, has theories.

Iwasaki explains that Long COVID is an umbrella term and likely has multiple mechanisms that are not mutually exclusive and may even coexist. She provided explanations for four predominant hypotheses being explored that may explain the condition.

1. Viral persistence: Growing research suggests that viral antigens and viral RNA, various proteins or genetic material, remain present and active in the bodys tissues following acute infection. A Harvard study, for example, found that the COVID-19 spike proteina protein vital in allowing the SARS-CoV-2 virus to infect cellscontinues to circulate in some Long COVID patients blood up to a year after infection. This protein can also be found in the blood of individuals who had COVID-19 but did not experience lingering symptoms.

Researchers in Iwasakis lab at YSM report that components of the SARS-CoV-2 virus, which causes COVID-19, may persist in the body, long after the initial infection is resolved. This persistence, explains Iwasaki, is thought to be due to a poor response to the initial viral SARS-CoV-2 infectioneither a delay in recognizing the virus or in alerting the bodys immune system of its presence, both leading to a late response.

2. Latent viral reactivation: There may be a connection between COVID-19 and some of the viral infections that many people have in childhood, specifically herpesviruses (a family of viruses including chickenpox) and/or Epstein-Barr virus (EBV, a virus that can cause mononucleosis and other illnesses). Some evidence suggests that COVID may reactivate these viruses, which generally lie dormant after the acute infection. The theory is that COVID-19 can cause immune system dysfunction, which then creates an opportunity for the previously dormant virus to re-emerge. Indeed, evidence of Epstein-Barr reactivation has been found in those with Long COVID.

3. Autoimmunity: Infection with the SARS-CoV-2 virus may trigger autoimmune disease. Elevated levels of autoantibodies, which are believed to play a role in other autoimmune conditions, such as lupus (SLE), rheumatoid arthritis, or Sjgrens syndrome, have been noted in some patients with Long COVID. Normally, antibodies respond to foreign invaders, such as bacteria and viruses. Autoantibodies instead can attack the bodys own cells, leading to inflammation and tissue injury.

In some patients with Long COVID, antinuclear autoantibodies (ANAs) have been identified up to 12 months after acute infection. These ANAs can target components of cell nuclei-promoting inflammation and damage organ systems. For example, in the inner lining of blood vessels known as the endothelium, these autoantibodies may promote a hyper-inflammatory state or changes to blood cells that might stimulate inappropriate clotting.

4. Inflammation: Inflammation, or recruiting white blood cells and the release of cytokines that initiate tissue swelling and injury, may also underlie some types of Long COVID. Mouse models suggest that the acute phase of infection alters tissue function and triggers chronic inflammatory states in cells, specifically long-lived cells in the brain. It is also possible that the three theories outlined aboveviral persistence, latent viral reactivation, and autoimmunityall contribute to the sustained inflammation seen in Long COVID.

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The Long COVID Puzzle: Autoimmunity, Inflammation, and Other Possible Causes - Yale Medicine