Study explains molecular basis of long-term COVID symptoms

NEW YORKJune 7, 2022 /PRNewswire/ — A new study provides a better understanding of how the pandemic virus causes depression, anxiety and loss of concentration known as “brain fog” in patients who develop COVID for a long time.

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

Led by researchers at the NYU Grossman School of Medicine, the study, which examined hamsters and human tissue samples, found that long after the initial viral infection was over, the most profound biological changes occur in the olfactory system, consisting of the nasal cavity, the specialized cells that line it, and the adjacent brain region that receives input for odors, the olfactory bulb. While a recent research 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 the sustained immune response in olfactory tissue affects brain centers that regulate 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 olfactory tissue, the study authors said. Unlike much of the COVID-19 research published to date, this study benchmarked how the response to SARS-CoV-2 in hamsters compared to influenza A, the virus responsible for ‘swine flu’. pandemic in 2009. Specifically, the study found that while the two 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 a month after viral clearance.

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

“Given the systemic scope of the findings, this study suggests that the molecular mechanism behind many long-term COVID-19 symptoms stems from this ongoing inflammation, while describing an animal model close enough to human biology to be useful in designing of future treatments,” says senior study author Benjamin tenOever, PhDprofessor in the departments of Medicine and Microbiology at NYU Langone Health.

Systemic Effects

SARS-CoV-2 and influenza A virus naturally infect both hamsters and humans — about 7-10 for both hosts, researchers say. In the current study, the authors looked at genetic and tissue changes at 3, 14, and 31 days post-infection to examine both 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, say, mice, with infections requiring the virus or mouse to be modified for the infection to take place.

The research team found that due to the idiosyncrasies in the way the virus copies itself, SARS-COV-2 likely triggers a stronger immune response than the same amount of influenza A, causing the greater scarring of SARS-COV-2 in the lungs and kidneys of patients. the hamsters 31 days after the initial infection.

The findings also confirmed that the prolonged immune responses seen in long-term COVID occur in tissues where the SARS-COV-2 virus is no longer present. One of the team’s theories is that damage from the initial infection left dead cell debris and viral RNA fragments, causing long-term inflammation. They also consider the possibility that the extensive damage to the olfactory cell lining, which is responsible for the loss of odor seen in SARS-CoV-2, could allow bacteria access to cells to which they would not normally be exposed (e.g. .), which would then trigger immune responses.

Whatever the cause, the chronic immune response in olfactory tissue of SARS-CoV-2 infected hamsters was associated with behavioral changes that the study authors tracked with established tests. For example, hamsters from the SARS-CoV-2 group stopped trying to swim more quickly, a degree of depression, or responded more quickly to foreign objects (marbles) in their cages, a behavior linked to fear. Depression and anxiety are common hallmarks of long-term COVID, and these behavioral abnormalities have been shown to correlate with unique changes in brain cell biology, the researchers say.

Outside of the brain, the authors examined the lungs one month after clearing the virus and after any acute lung infection. They found that in the wake of SARS-COV-2, airway reconstruction was significantly slower than influenza A — a consequence of COVID-19 causing more damage. Examinations of tissue slides under a microscope also showed lung scarring, which was more widespread in SARS-COV-2 infected lungs, which could partially explain the shortness of breath seen in some tall COVID patients. The study also found that the inflammatory response to SARS-COV-2 resulted in damage to the kidneys that lasted longer than damage caused by infection with the influenza A virus.

Together with tenOever, study authors from the Department of Microbiology at NYU Langone Health were the first author Justin FrereKohei OishicIlona GolynkerMaryline PanisShu Horiuchi, and Rasmus Moller. Other authors included Daisy Hoaglandnow on Harvard Universityand Randal SerafiniKerri PryceaJeffrey ZimeringAnne Ruiz, and Venetia Zachariou in the Department of Neuroscience; like Jonathan Overdevest in the Neurosurgery Department. Study authors of University of Columbia were Marianna Zazhytska, Albana Kodra, and Stavros Lomvardas of Mortimer B. Zuckerman Mind, Brain and Behavior Institute; like Peter Canoll of the Department of Pathology and Cell Biology. Study authors of Weill Cornell Medicine 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 by the generous support of the Zegar Family Foundation to the tenOever lab 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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