Cell surface α2,3-linked sialic acid facilitates Zika virus internalization

Area of Science:

• Virology
• Cell Biology
• Pathogenesis

Background:

• Neurotropic Zika virus (ZIKV) poses a global public health threat, causing microcephaly through placental barrier crossing.
• The precise mechanism of ZIKV entry into host cells remains unclear, with AXL's role as an interferon antagonist rather than an entry receptor.

Purpose of the Study:

• To investigate the role of cell surface sialic acid in ZIKV infection.
• To elucidate the mechanism by which sialic acid influences ZIKV entry and pathogenesis.

Main Methods:

• Enzymatic removal of sialic acid using neuraminidase.
• Genetic knockout of sialic acid biosynthesis and linkage-specific genes (e.g., UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase, ST3 β-galactoside-α2,3-sialyltransferase 4).
• Pronase treatment to distinguish attachment from internalization, and sialyllactose inhibition studies.

Main Results:

• Removal of sialic acid significantly reduced ZIKV infection in Vero cells and neural progenitor cells.
• Knockout of sialic acid biosynthesis genes decreased ZIKV infection for both African and Asian lineages.
• Deficiency in α2,3-linked sialic acid reduced ZIKV infection, indicating its importance in viral internalization, not attachment.

Conclusions:

• Cell surface sialic acid, particularly α2,3-linked forms, is a critical host factor mediating ZIKV internalization.
• Sialic acid likely facilitates ZIKV-receptor complex internalization rather than direct viral binding.
• This finding offers novel insights into ZIKV pathogenesis and potential therapeutic targets.