Reovirus genomic diversity confers plasticity for protease utility during adaptation to intracellular uncoating

Reoviruses infect many mammals and are widely studied as a model system for enteric viruses. However, most of our reovirus knowledge comes from laboratory strains maintained on immortalized L929 cells. Herein, we asked whether naturally circulating reoviruses possess the same genetic and phenotypic characteristics as laboratory strains. Naturally circulating reoviruses obtained from sewage were extremely diverse genetically. Moreover, sewage reoviruses exhibited poor fitness on L929 cells and relied heavily on gut proteases for viral uncoating and productive infection compared to laboratory strains. We then examined how naturally circulating reoviruses might adapt to cell culture conditions. Within three passages, virus isolates from the parental sewage population were selected, displaying improved fitness and intracellular uncoating in L929 cells. Remarkably, selected progeny clones were present at 0.01% of the parental population. Altogether, using reovirus as a model, our study demonstrates how the high genetic diversity of naturally circulating viruses results in rapid adaptation to new environments.