Nelson Bay Orthoreovirus cell attachment protein σC determines strain-specific differences in infectivity and pathogenesis

Nelson Bay orthoreovirus (NBV) was initially discovered in a bat sample but has since been isolated from patients with acute respiratory tract diseases. Accumulating reports of NBV isolation from patients with respiratory tract viral infections suggest that NBV is able to transmit and cause disease in humans. However, the underlying molecular mechanisms remain unclear. We previously established a reverse genetics system for NBV Miyazaki-Bali/2007 (MB) strain isolated from a patient with an acute respiratory tract disease. We found that the fusion-associated small transmembrane protein (FAST)-which is necessary for syncytium formation-and cell attachment protein σC play crucial roles in MB virulence; however, whether these gene products determine the strain-specific difference in NBV virulence remains unclear. Therefore, here, we compared the virulence of the MB strain with that of the NBV strain isolated from a bat sample (NelB strain). We found that the NelB strain did not cause a virulent phenotype in the mouse model. Using reverse genetics, we found that the S1 gene segment correlates with the virulent phenotypes of NBV strains. Moreover, among the three proteins encoded by the S1 gene segment, structural protein σC, but not nonstructural proteins FAST or p17, contributed to the difference in virulence in vivo. Further analysis using a panel of σC mutant viruses showed that the middle body domain in σC was involved in the different virulent phenotypes, rather than the C-terminal head domain, which contains a putative receptor-binding domain. These results provide new insights into the mechanisms underlying NBV transmission and pathogenesis.