Unveiling Paramyxovirus Glycan Preference: Investigating Paramyxovirus- Sialoglycan Interactions Across Diverse Glycan Types

Abstract

Understanding the intricate interplay between viruses and sialoglycan receptors is pivotal for elucidating the multifaceted mechanisms governing viral tropism, replication efficiency, and pathogenesis. Among viral pathogens, paramyxoviruses maintain a delicate equilibrium, skillfully evading sialylated decoy receptors while efficiently exploiting sialoglycan receptors with heightened affinity to invade host cells. The hemagglutinin-neuraminidase (HN) protein, a common glycoprotein among certain paramyxoviruses, plays a critical role in receptor recognition and binding through its hemagglutinin and neuraminidase activities. Our research focused on sialoglycan receptors' role in paramyxoviral infection, probing the specific sialic acid linkages and glycan structures involved. We explored the specific sialic acid linkages and glycan structures involved in virus-receptor interaction. Infection assays employing glycosyltransferase knock-out cell lines revealed the significance of different glycan structures in viral infection, noting distinct preferences among different paramyxoviruses. We discovered that the absence of sialylation on the ∆Sia cell line rendered it resistant to infection by certain paramyxoviruses. However, Newcastle disease virus (NDV), surprisingly, was still capable of infecting cells lacking sialylation, suggesting alternative binding mechanisms. All viruses studied preferred entry of cells displaying α2-3 linked over α2-6 linked sialic acids. Furthermore, we found that the composition of glycans, different types of sugar chains, played a critical role in viral infection. Cells with specific glycans showed higher infection rates for certain viruses. For instance, cells with sialylated glycolipids were more susceptible to SeV and hPIV3 compared to NDV and hPIV1. Furthermore, restoring the sialylation by various sialyltransferases revealed the specific sialylated glycan structures crucial for viral infection, emphasizing the significance of α2-3-linked sialic acids on N-glycans for Sendai virus (SeV), human parainfluenza virus 1 and 3 (hPIV1 and hPIV3), and NDV, and the potential involvement of O-glycans and glycolipids for NDV. Additionally, we investigated the impact of the α2-3 to α2-6 linked sialic acid ratio on viral infectivity and explored the role of fucosylation in viral infection. Our results suggest that the ratio of α2-3 to α2-6 linked sialic acids plays a crucial role in determining the infectivity of paramyxoviruses, with a lower α2-3/α2-6 ratio negatively affecting infection with of SeV, hPIV3, and hPIV1, but not NDV. Moreover, the presence of fucose-containing glycotopes (sLex) exerted varying effects on the infectivity of different paramyxoviruses. Overall, our study illuminates the complex receptor interactions governing paramyxoviral infections and their implications for viral pathogenesis and zoonotic potential. The recognition of specific glycan structures by these viruses underscores the need to consider receptor diversity in the context of viral infection. The potential for paramyxoviruses to cross species barriers necessitates further investigation, refining our comprehension of viral host range and tropism.