Study explains molecular basis of long COVID symptoms

NEW YORK, June 7, 2022 /PRNewswire/ — A new study sheds light on how the pandemic virus causes depression, anxiety and loss of concentration known as “brain fog” in patients who develop long-term COVID.

In most individuals, the virus, SARS-CoV-2, is successfully cleared by the immune system, but some struggle with prolonged complications, the cause of which is unknown.

Led by researchers at NYU Grossman School of Medicine, the study, which looked at hamsters and human tissue samples, found that long after the initial viral infection subsides, the most profound biological changes occur. produce in the olfactory system, consisting of the nasal cavity, the specialized cells that line it, and the adjacent brain region that receives information about smells, the olfactory bulb. While a recent study from the same lab showed how SARS-COV-2 infection impairs the sense of smell by altering the activity of certain olfactory proteins (receptors), the new study reveals how sustained immune response in olfactory tissue affects brain centers that govern emotion and cognition.

Published online June 7 in Science Translational Medicine, the study is the first to show that hamsters previously infected with SARS-CoV-2 develop a unique inflammatory response in the olfactory tissue, say the study authors. Unlike most COVID-19 research published to date, this study compared the response to SARS-CoV-2 in hamsters to influenza A, the virus responsible for the ‘swine flu’ pandemic in 2009. Specifically, the study found that while both viruses generated a similar response in the lungs, only SARS-CoV-2 triggered a chronic immune response in the olfactory system that was still evident one month after viral clearance. .

This chronic inflammatory state seen with SARS-CoV-2 corresponded to an eruption of immune cells such as microglia and macrophages, which clean up debris left in the wake of the lining of dead and dying olfactory cells. They recycle this material but also trigger additional production of cytokines, pro-inflammatory signaling proteins. This biology was also evident in olfactory tissue removed during autopsies from patients who had recovered from the initial COVID-19 infections, but who had died of other causes.

“Given the systemic significance of its findings, this study suggests that the molecular mechanism underlying many of the prolonged symptoms of COVID-19 stems from this persistent inflammation while describing an animal model close enough to human biology to be useful. in the design of future treatments,” says the study’s lead author. Benjamin tenOever, PhDprofessor at the Departments of Medicine and Microbiology at NYU Langone Health.

Systemic effects

SARS-CoV-2 and the influenza A virus naturally infect hamsters and humans – lasting about 7 to 10 for both hosts, the researchers say. In the present study, the authors examined genetic and tissue changes at 3, 14, and 31 days after infection to examine acute and persistent responses to these infections. Previous studies had shown that the golden hamster model copies the human biological response to SARS-COV-2 better than mice, for example, in which infections require the virus or mouse to be modified for infection to occur. .

The research team found that SARS-COV-2, due to quirks in the way the virus copies itself, likely elicits a stronger immune response than the same amount of influenza A, which may explain the greater scarring caused by SARS-COV-2 in the lungs and kidneys of hamsters 31 days after initial infection.

The results also confirmed that the prolonged immune responses seen in long COVID occur in tissues where the SARS-COV-2 virus is no longer present. One of the team’s theories is that the damage from the initial infection left remnants of dead cells and fragments of viral RNA, which cause prolonged inflammation. They also consider the possibility that the extensive damage to the lining of olfactory cells, responsible for the loss of smell seen with SARS-CoV-2, may allow bacteria access to cells to which they would not normally be exposed ( for example, brain cells in the bulb), which would then trigger immune reactions.

Whatever the cause, the chronic immune response in the olfactory tissues of SARS-CoV-2-infected hamsters was accompanied by behavioral changes that the study authors tracked with established tests. For example, hamsters in the SARS-CoV-2 group were faster to stop trying to swim, a measure of depression, or to react to foreign objects (marbles) in their cages, a behavior linked to anxiety. Depression and anxiety are common attributes of long COVIDs, and these behavioral abnormalities have been shown to correlate with unique changes in brain cell biology, the researchers say.

Beyond the brain, the authors examined the lungs one month after virus clearance and after each acute lung infection. They found that following SARS-COV-2, airway reconstruction was significantly slower than with influenza A – due to COVID-19 causing greater damage. Microscopic tissue slide examinations also showed scarring in the lungs that was more prevalent in SARS-COV-2 infected lungs, which may partly explain the shortness of breath seen in some long-term COVID patients. . The study also found that the inflammatory response to SARS-COV-2 led to kidney damage that lasted longer than the damage caused by the influenza A virus infection.

With tenOever, study authors from the NYU Langone Health Department of Microbiology were first author Justin Brother, Kohei Oishi, Ilona Golynker, Maryline Panis, Shu Horiuchi, and Rasmus Moller. Other authors included Marguerite HoaglandNow to Harvard Universityand Randal Serafini, Kerri Price, Jeffrey Zimering, Anne Ruiz, and Venetia Zachariou from the Department of Neuroscience; as good as Jonathan Overdevest in the neurosurgery department. Authors of studies of Colombia University were Marianna Zazhytska, Albana Kodra, and Stavros Lomvardas of Mortimer B. Zuckerman Mind, Brain and Behavior Institute; as good as Pierre Canol of the Department of Pathology and Cellular Biology. The authors of the Weill Cornell Medicine study were Alain Borczuk in the Department of Pathology and Laboratory Medicine, and Vasuretha Chandar, Yaron Bramand Robert Schwartz in the Department of Physiology, Biophysics and Systems Biology.

This work was funded through the generous support of the Zegar Family Foundation to the tenOever Laboratory and funding from National Institutes of Health grants NS111251, NSO86444, and NSO86444S1.

Contact:
Gregory Williams
[email protected]

SOURCE NYU Grossman School of Medicine and NYU Langone Health

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