Envelope protein residue E152 confers enhanced GAS6-dependent cell entry to the African Zika virus strain MR766

Zika virus (ZIKV) is a mosquito-borne flavivirus that was first isolated in Africa and subsequently spread through Asia to the Pacific region and the Americas, causing large outbreaks associated with fetal microcephaly and other neurological disorders, including Guillain-Barré syndrome. ZIKV lineages are broadly classified into African and Asian strains, with all strains responsible for large-scale epidemics belonging to the Asian lineage. Nevertheless, accumulating evidence indicates that African strains show higher viral replication, stronger inflammatory responses, and greater pathogenicity than Asian strains. In this study, we employed single-round infectious particles (SRIPs) to quantitatively assess viral entry into host cells and demonstrated that SRIPs derived from the African strain MR766 exhibit markedly higher cell entry ability than those derived from the Asian strain PRVABC59 SRIPs. Using chimeric and mutant SRIPs, we identified a single amino acid at position 152 in the envelope protein (E152) of MR766 as a key determinant of enhanced viral entry. Mechanistically, the MR766 E protein showed stronger binding affinity to growth arrest–specific 6 (GAS6), a ligand for AXL and other TAM receptor family members, thereby facilitating efficient cellular entry. These findings uncover a molecular basis underlying the enhanced entry efficiency and pathogenicity of African ZIKV strains and provide insights that may inform the design of antiviral strategies targeting the GAS6–TAM axis, as well as the development of ZIKV vaccine platforms with optimized antigenic properties.