Examining the direct and indirect effects of acute respiratory virus infection on the central nervous system

Abstract

Viral pandemics caused by influenza viruses and coronaviruses have led to significant disease and economic burden globally. Beyond their acute impact on health, these infections are increasingly implicated in long-term neurological complications and may contribute to neurodegenerative diseases. Therefore, understanding the impact of these infections on neuropathology and ultimately neurodegeneration is critical for developing effective treatments to mitigate their impact. First, we investigated the influence of common acute viral infection, such as those caused by influenza A virus (IAV) and SARS-CoV-2, on amyotrophic lateral sclerosis (ALS) disease progression. While several viral infections have been associated with ALS, most prior studies have focused on chronic and/or neurotropic infections. The influence of acute non-neurotropic infections on ALS and mechanisms responsible for potentiating disease remain elusive. Using a mouse model of ALS, we demonstrate that acute respiratory infection with IAV during the presymptomatic stages of ALS led to accelerated disease progression. This virally-induced acceleration of disease was accompanied by increased gliosis and upregulation of transcriptional pathways involved in inflammatory responses, metabolic dysregulation, and muscular dysfunction. Therapeutic suppression of gliosis or administration of a direct-acting antiviral was associated with significantly improved ALS clinical signs. We also demonstrate that acute infection with SARS-CoV-2 results in similar disease acceleration. Second, we performed genome-wide CRISPR screens (GWCSs) in central nervous system (CNS)-derived cells to identify host genes conferring susceptibility to seasonal human coronaviruses (HCoVs). This approach identified susceptibility genes and pathways that are both common and unique to seasonal HCoV infection, and aligned with host pathways previously indicated in non-CNS cells. Additionally, we identified novel host genes, including MDH1 and NXPE3, that promote infection in CNS-derived cells. Lastly, from our GWCSs, we identified the unfolded protein response (UPR) and autophagy as key pathway causing susceptibility to HCoV infection in CNS-derived cells. We investigated the therapeutic efficacy of inhibiting the UPR in preventing virus-induced cell death in CNS-derived cells. We demonstrate that inhibiting the UPR using the small molecule inhibitors MKC9989 and tauroursodeoxycholic acid (TUDCA) resulted in protection from HCoV-OC43- and SARS-CoV-2-induced cell death, which was independent of restricting viral replication. Furthermore, induction of autophagy resulted in protection from SARS-CoV-2 infection, but had no effect following HCoV-OC43 infection – highlighting that HCoVs with similar biologies can have different host cell requirements. Together, these studies advance our understanding of how viral infections contribute to neuropathology and propose novel therapeutic approaches to protect the CNS from current and future IAV and HCoV outbreaks.