Rethinking the Drivers of Coronavirus Virulence and Pathogenesis: Toward an Understanding of the Dynamic World of Mutations, Indels, and Recombination Within the Species Alphacoronavirus-1

Alphacoronaviruses are widespread but understudied in comparison to betacoronaviruses. Recombination, mutations, and indels are hallmarks of coronavirus replication, which together facilitate viral spillover and emergence, especially within the alphacoronaviruses. The species _Alphacoronavirus-1_ comprises distinct viruses of cats, dogs and pigs. In cats, high-pathogenicity feline coronavirus (FCoV) is infamous as the cause of feline infectious peritonitis (FIP), a lethal disease that can now be treated with antiviral drugs. FCoV-1 exists as two distinct genotypes (type -1 and -2) and is transmitted as a low-pathogenicity virus that causes mild or asymptomatic disease. The high-pathogenicity FCoV variants arise in cats already infected with FCoV, and while the mutations responsible for this phenotype change remain enigmatic, the main determinant of pathogenicity is the viral spike glycoprotein. FCoV-1 disease outcome is driven by a combination of both within- and between-host evolution, whereas FCoV-2 disease appears to be driven by recombination with co-circulating canine coronaviruses (CCoV). FCoV-1 virulence can be largely explained using the “furin cleavage site (FCS) disruption hypothesis,” which argues that low-pathogenicity FCoV-1 contains an intact FCS while high-pathogenicity FCoV-1 has a disrupted FCS that is unable to be cleaved. FCoV-2 virulence and pathogenesis is exemplified by FCoV-23, a novel canine/feline recombinant virus that caused a widespread outbreak of severe disease in Cyprus during 2023. As such, _Alphacoronavirus-1 _mayexist as adynamic "metavirome"1 that is in a constant state of flux, presenting notable challenges for disease surveillance and management, and in risk-assessment.