Q&A: The science behind long COVID symptoms

New research seems to help explain the biology behind long COVID symptoms like brain fog and increased anxiety and depression.

In a study published in Science Translational Medicine, researchers discovered that an immune reaction in olfactory tissue is affecting brain centers that control emotion and cognition.

Justin J. Frere, an MD/PhD student at the Icahn School of Medicine at Mount Sinai, and colleagues compared the response to SARS-CoV-2 vs. influenza A in tissue samples. The researchers reported that both viruses generated similar responses in lung tissue; however, only SARS-CoV-2 triggered a chronic immune response in the olfactory system that persisted 1 month after viral clearance.

Healio spoke with Frere about why SARS-CoV-2 causes long-term symptoms and how the new study findings could help inform future research on treatment targets.

Healio: What's the simplest way to explain to patients the reasons why SARS-CoV-2 causes symptoms like brain fog, depression and anxiety after the acute phase of infection is over?

Frere: During its initial infection, SARS-CoV-2 causes a massive immune response that extends across almost every part of the body. This systemic response to the virus — even though it makes us feel sick — is what allows us to eventually eliminate the virus from our bodies. This is a process which occurs with many infections, and in our study, we see a similar process happening in the body's response to influenza. With normal infections, once the pathogen is cleared, the immune response isn't necessary anymore, and it will quickly fade, returning your body to a normal, non-sick state; however, with SARS-CoV-2, while most of the systemic immune response fades when the virus is cleared, there is a small area of the brain called the olfactory bulb in which this immune response seems to persist for quite a long time, even after the infection is gone. Long-term immune responses and associated inflammation in the brain can cause the nervous system to act abnormally, leading to the development of symptoms such as brain fog, depression and anxiety. We thus believe that this persistent immune response in the brain caused by SARS-CoV-2 infection may be a major contributor to the development of some of the cognitive and behavioral symptoms seen in long COVID patients. This being said, we still have a lot of work to do to confirm the specifics of what is happening here. SARS-CoV-2 can cause damage to the body in a variety of ways, and this makes it possible — if not likely — that this persistent inflammation is only one of several processes by which the virus can cause these long COVID symptoms.

Healio: What are the implications of your findings?

Frere: Our study highlights a unique molecular process caused by SARS-CoV-2 that may underlie some of the cognitive symptoms associated with long COVID. In defining this process, we hope that it serves as a potential target that can be therapeutically treated in long COVID patients — hopefully alleviating or preventing the development of these symptoms. Furthermore, we show that hamsters can display persistent symptomology and pathologic processes in response to SARS-CoV-2 infection, potentially mimicking similar processes that may be occurring in individuals that suffer from long COVID. This makes hamsters a potential model in which we can trial new long COVID therapeutics. This will hopefully make it easier to identify drugs that can treat this condition.

Healio: How could these new findings impact future research on potential therapeutic targets?

Frere: We think that our research highlights a potential therapeutic target that we may be able to effectively treat with drugs. Further, in our study, we showed the hamster to be a potential animal model for long COVID, and as such, we hope that we can leverage this knowledge to test out new therapeutics against long COVID in hamsters. As new long COVID therapeutic targets are identified, we hope that others will be able to test new drugs against these targets in the hamster model to more quickly identify effective treatments for the disease.

Healio: What are the next steps of your research?

Frere: First, we're really hoping to explore this persistent olfactory inflammation phenomenon further in human patients. Further, we hope to start trialing drugs in hamster model to see if we can successfully alleviate any behavioral alterations induced by SARS-CoV-2 infection. We'd love to test Paxlovid and corticosteroids to see if either of these drugs can successfully alleviate the persistent inflammation that we see and in turn alleviate the behavioral abnormalities we note in the hamsters.

Healio: Is there anything else you’d like to add?

Frere: In comparing our results from SARS-CoV-2-infected hamsters side by side to results from influenza-infected hamsters, we present one of the first studies by which we can benchmark SARS-CoV-2 infection against other pandemic-associated pathogens. In doing this, we were able to not only get a better understanding of the severity caused by SARS-CoV-2 infection, but really highlight processes uniquely induced by SARS-CoV-2.

Reference:

• Frere, J, et al. Science Translational Medicine. 2022;doi:10.1126/scitranslmed.abq3059
• Study Explains Molecular Basis of Long COVID Symptoms. https://nyulangone.org/news/study-explains-molecular-basis-long-covid-symptoms. Published June 7, 2022. Accessed Jun 17, 2022.