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

Sialic acids (SAs) are abundantly expressed on vertebrate cell surfaces and are widely recognized as key viral attachment factors, particularly for influenza viruses. However, their role remains understudied in other orthomyxoviruses, such as thogoto and quaranja viruses, which are tick-borne viruses sporadically infecting humans. Enzymatic removal of SAs increased the infectivity of Thogoto and Dhori viruses, as well as pseudotypes carrying the glycoproteins of Oz, Sinu, and Wellfleet Bay viruses. A similar effect on pseudotype infectivity was observed following the binding of specific lectins to SAs. These findings indicate that, in contrast to influenza viruses, SAs act as a barrier to the entry of these orthomyxoviruses. Experimental evolution of the Sinu and Wellfleet Bay virus glycoproteins revealed point mutations that partially overcame this barrier. Given the abundance of sialic acids in mucosal tissues, we speculate that SAs may contribute to the inability of thogoto and quaranjaviruses to transmit directly between vertebrate hosts. Our results also underscore the importance of monitoring the circulation of these viruses for potential changes in their transmission routes. Author summary Many viruses, including influenza viruses, use sugar molecules called sialic acids (SAs) on the surface of host cells to promote viral entry. Here, we show that SAs can instead restrict infection for several lesser-known relatives of influenza virus that are primarily transmitted by ticks and can occasionally infect humans. Removal of SAs from human cells strongly increased entry of these non-influenza viruses, when using both non-replicative pseudotypes and authentic viruses. In addition, masking SAs also enhanced entry of viral pseudotypes. We further found that viral surface proteins can acquire mutations that partially reduce this restriction, indicating an ability by these viruses to adapt to SA–rich environments. Because SAs are abundant in vertebrate mucosal tissues such as the respiratory tract, our findings suggest a possible explanation for why these viruses do not transmit directly between vertebrate hosts and rely on tick bites for infection. More broadly, this work identifies a previously unrecognized host cell surface feature that limits viral entry and highlights the importance of monitoring viral evolution that could alter transmission potential.