Identification of Transmembrane and Extracellular Host Proteases that Promote Human CoV Entry and Syncytium Formation

Abstract

Coronaviruses (CoVs) comprise a family of enveloped viruses that cause respiratory disease in humans, including CoV disease 2019 (COVID-19), caused by severe-acute respiratory syndrome CoV-2 (SARS-CoV-2). For CoV infection to occur, the CoV spike (S) protein must mediate fusion between the viral and host membranes. This entry process can also be repurposed during infection to promote cell-to-cell fusion, further contributing to viral spread. To trigger fusion, S must bind its cognate receptor and be cleaved by host proteases. Identifying cellular proteases capable of triggering CoV fusion is critical to understand CoV entry, tropism, and cell-cell spread, however the range of proteases capable of promoting CoV fusion has not been fully explored. Here, using fusion and entry assays, I provide evidence implicating matrix metalloproteinase-9 (MMP-9) as a fusion trigger for SARS-CoV-2 and HCoV-229E. Additionally, I show MMP-9 expression is upregulated during CoV infection, highlighting its potential relevance as a CoV triggering factor.