Role of cell surface sialic acid in Zika virus internalization Chee Wah Tan1, Catherine Hong Huan Hor2, Swee Sen Kwek1, Han Kang Tee3, I-Ching Sam3, Eyleen L. K. Goh2, Eng Eong Ooi1, Yoke Fun Chan3, Lin-Fa Wang1* 1Programme in Emerging Infectious Diseases, Duke-NUS Medical School, 169857 Singapore; 2Neuroscience Academic Clinical Programme, Duke-NUS Medical School, 169857 Singapore; 3Department of Medical Microbiology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Emergence of neurotropic Zika virus (ZIKV) raised a public health emergency of global concern. With recent findings reporting AXL as a type I interferon antagonist rather than an entry receptor, the exact mechanism underlying the entry of ZIKV, and flaviviruses in general, remains unresolved. Here we report that cell surface sialic acid plays an important role in ZIKV infection. Removal of cell surface sialic acid by neuraminidase significantly abolished ZIKV infection in Vero cells and human induced pluripotent stem cells-derived neural progenitor cells. Furthermore, knockout of the sialic acid biosynthesis gene encoding UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) resulted in significantly reduced infection for both the African and Asian ZIKV lineages. Removal of membrane-bound, un-internalized virus with pronase treatment confirmed that sialic acid is required for ZIKV internalization but not attachment. Sialyllactose inhibition study showed that there is no direct interaction between sialic acid and ZIKV particles, implying that sialic acid could be mediating ZIKV-receptor complex internalization. Identification of sialic acid as an important host factor for ZIKV internalization provides a new insight into better understanding on ZIKV infection and pathogenesis.
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