Sequence similarity between SARS-CoV-2 Nucleocapsid and CNS proteins provides mechanistic insight into viral neuropathogenesis following infection

Abstract

Abstract The novel coronavirus SARS-CoV-2 emerged in 2019 and continues to cause death and disease throughout the world. To date, there have been 272 million infections and 5.3 million deaths worldwide, underscoring the necessity of understanding the virus and host immune response as well as developing novel therapeutics for severe disease. From the start of the pandemic, a prominent pattern of central nervous system (CNS) pathologies – including cases similar to Multiple Sclerosis (MS) - has emerged that suggest a related, underlying mechanism of viral mimicry to proteins expressed by CNS tissues. We hypothesized that immunodominant epitopes of SARS-CoV-2 share homology with proteins typically associated with MS. Using Pepmatch, a bioinformatics package which predicts peptide similarity in the context of MHC presentation, we discovered that Nucleocapsid protein, but not Spike or Membrane proteins, of SARS-CoV-2 shares significant overlap with 22 MS-associated proteins. To provide further physiological relevance, we used an MHC binding prediction tool to determine whether these Nucleocapsid peptides would bind preferentially to MS-associated alleles. While we did not find any significant binding pattern among MS-associated alleles, we did discover that Nucleocapsid peptides which overlap with CD99 Antigen were among the top HLA-peptide predictions. This finding provides a plausible mechanism by which the targeting of CD99 by lymphocytes leads to compromised blood-brain-barrier integrity and exacerbated viral neuropathogenesis. This work provides a deeper understanding of the unique viral dynamics with the human immune system and corroborates the targeting of CD99 to ameliorate neurological complications of SARS-CoV-2.