Potential differences in cleavage of the S protein and type-1 interferon together control human coronavirus infection, propagation, and neuropathology within the central nervous system.

Human coronaviruses (HCoV) are respiratory pathogens which have been known since the 1960's. In December 2019, a new betacoronavirus, SARS-CoV-2, was reported and is responsible for one of the biggest pandemics of the last two centuries. Similar to the HCoV-OC43 strain, available evidence suggests SARS-CoV-2 neuroinvasion associated with potential neurological disorders. Coronavirus infection of the central nervous system (CNS) is largely controlled by a viral factor, the spike glycoprotein (S) and a host factor, innate immunity. However, the interaction between these two factors remains elusive. Proteolytic cleavage of the S protein can occur at the interface between receptor binding (S1) and fusion (S2) domains (S1/S2), as well as in a position adjacent to a fusion peptide within S2 (S2'). Herein, using HCoV-OC43 as a surrogate for SARS-CoV-2, we report that both S protein sites are involved in neurovirulence and are required for optimal CNS infection. Whereas efficient cleavage at S1/S2 is associated with decreased virulence, the potentially cleavable putative S2' site is essential for efficient viral infection. Furthermore, type 1 interferon (IFN 1)-related innate immunity also plays an important role in the control of viral spread towards the spinal cord, by preventing infection of ependymal cells. Our results underline the link between the differential S cleavage and IFN 1 in the prevention of viral spread, to control the severity of infection and pathology in both immunocompetent and immunodeficient mice. Taken together, these results point towards two potential therapeutic anti-viral targets: cleavage of the S protein in conjunction with efficient IFN 1-related innate immunity to prevent or at least reduce neuroinvasion, neural spread, and potential associated neurovirulence of human coronaviruses.