SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found capable of inducing long term effects commonly referred to as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. To define the molecular basis of this condition, we compared the short- and long-term responses to influenza A virus and SARSCoV-2 in the golden hamster model. These data demonstrated that SARS-CoV-2 resulted in sustained changes to lung, kidney, and brain. The most significant change in response to SARS-CoV-2 was observed in the olfactory bulb, where persistent inflammation was visible beyond one month post infection. This was characterized by microglial activation, pro-inflammatory cytokine production, and a Type I interferon (IFN-I) response in the absence of detectable virus. Given the connection between olfactory bulb injury and neurological disorders, we postulate that this prolonged inflammation is an underlying cause of long COVID.
Funding Information: This work was funded by generous support from the Marc Haas Foundation, the National Institutes of Health (NCI (R01CA234614) and NIAID (2R01AI107301) and NIDDK (R01DK121072 and 1RO3DK117252) to Department of Medicine, Weill Cornell Medicine (R.E.S.)), and DARPA’s PREPARE Program (HR0011-20-2-0040). The work was further funded by NINDS (NS111251, NSO86444, NSO86444S1)(V.Z., R.A.S.).
Ethics Approval Statement: The Tissue Procurement Facility operates under Institutional Review Board (IRB) approved protocol and follows guidelines set by Health Insurance Portability and Accountability Act (HIPAA). Experiments using samples from human subjects were conducted in accordance with local regulations and with the approval of the IRB at the Weill Cornell Medicine. The autopsy samples are considered human tissue research and were collected under IRB protocols 20-04021814 and 19-11021069. All autopsies have consent for research use from next of kin, and these studies were determined as exempt by IRB at Weill Cornell Medicine under those protocol numbers.
Frere, Justin J. and Serafini, Randal A. and Pryce, Kerri D. and Golynker, Ilona and Panis, Maryline and Zimering, Jeffrey and Horiuchi, Shu and Hoagland, Daisy A. and Moeller, Rasmus and Oishi, Kohei and Ruiz, Anne and Borczuk, Alain and Chandar, Vasuretha and Bram, Yaron and Park, Jiwoon and Foox, Jonathan and Meydan, Cem and Mason, Christopher E. and Schwartz, Robert E. and Zachariou, Venetia and tenOever, Benjamin R., A Molecular Basis of Long COVID-19. Available at SSRN: https://ssrn.com/abstract=3885245 or http://dx.doi.org/10.2139/ssrn.3885245
This version of the paper has not been formally peer reviewed.