Sialic acids are a barrier to the entry of non-influenza orthomyxoviruses

This study explored how cell surface sialic acids (SAs) influence the entry of thogoto- and quaranjaviruses, a group of non-influenza orthomyxoviruses. Using pseudotyped vesicular stomatitis virus (VSV) and lentiviral systems expressing viral glycoproteins, alongside authentic Thogoto (THOV) and Dhori (DHOV) viruses, the authors evaluated viral entry under conditions of altered SA availability. Enzymatic removal of SAs or their masking with lectins consistently enhanced viral entry, in sharp contrast to influenza viruses, where SAs serve as essential receptors. Further analyses across multiple cell lines revealed an inverse relationship between SA abundance and viral entry efficiency, indicating that SAs act as inhibitory factors rather than facilitators. These findings were corroborated in primary human airway epithelial cells and with infectious virus assays, where depletion of SAs significantly increased viral replication. In addition, adaptive mutations identified through experimental evolution partially mitigated this restriction, suggesting that viral glycoproteins can evolve to counteract SA-mediated inhibition. Overall, the study uncovers a distinct entry mechanism for these viruses and highlights sialic acids as a natural barrier to infection, offering new insights into host restriction, viral adaptation, and transmission dynamics.
(TMR)