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100 envelope challenge in 100 days12/25/2023 ![]() ![]() Here, combining reverse genetics, animal experiments, and biochemical assays, we aimed to identify the molecular neurovirulent determinants of the African lineage. Nevertheless, viral determinants and underlying mechanisms responsible for the phenotypic differences remain largely unknown currently. ZIKV structural genes have been reported to determine the virulence of African and Asian lineages 24. Furthermore, African ZIKV isolates caused more rapid and more severe cytopathic effects (CPE) and replicated more efficiently than Asian isolates in multiple cell lines 22, 23. For example, when compared to Asian strains, African strains infected human NSCs and astrocytes more efficiently, and caused greater levels of apoptosis 20, 21. ![]() Significantly, comparative studies based on cell culture experiments and animal models have shown that African lineage viruses were more virulent than Asian lineage viruses 14, 15, 16, 17, 18, 19. Contemporary Asian lineage ZIKV has acquired multiple adaptive mutations during its circulation to enhance its transmissibility from mosquitoes to humans 12 and tropism to human neural progenitor cells (NPC) 13. To date, the African lineage has exclusively been detected in the African continent 8, 9, whereas the majority of recent epidemics in the South Pacific and Americas are attributed to the Asian lineage 10, 11. Phylogenetic analysis shows that ZIKV strains are classified into two major lineages referred to as the ancestral African lineage and the contemporary Asian lineage, respectively 7. The structural proteins are responsible for virus assembly, while the nonstructural proteins are involved in the replication of the viral RNA genome. The ORF produces a polyprotein, which is subsequently processed by viral and host proteases to produce a total of three structural proteins (capsid (C), pre-membrane/membrane (prM/M), and envelope proteins (E)) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The ZIKV genome is a positive-sense single-stranded RNA, which consists of a single open reading frame (ORF) flanked by 5′ and 3′ untranslated regions (UTR). Currently, no antiviral agents and vaccines have been approved for use in preventing and treating ZIKV infection. Although ZIKV transmission has waned in the Americas, outbreaks and infection clusters continue to emerge in Asia, India, and Africa 6. On February 1 st, 2016, the World Health Organization (WHO) declared ZIKV outbreaks a public health emergency of international concern. It is noteworthy, however, during the 2015–2016 outbreak in the Americas, ZIKV spread into 84 different countries worldwide, with an estimated total of over 1.5 million cases, including thousands of microcephaly cases and other congenital malformations now termed congenital Zika syndrome (CZS) 4, 5. Originally isolated in 1947 in the Zika forest of Uganda, Africa 1, ZIKV was neglected for many years, as only sporadic human infections were documented in Africa and Asia 2, 3. The mosquito-transmitted Zika virus (ZIKV) is a member of Flavivirus genus in the family Flaviviridae, which includes a number of well-known human pathogens such as yellow fever virus (YFV), dengue virus (DENV), West Nile virus (WNV), and Japanese encephalitis virus (JEV). Our study identifies the role of K101R substitution in the C protein in contributing to the enhanced virulent phenotype of the African lineage ZIKV, which expands our understanding of the complexity of ZIKV proteins. Finally, a combined analysis reveals the K101R substitution promotes the production of mature C protein without affecting its binding to viral RNA. Moreover, K101R replicates more efficiently in mouse brains and induces stronger inflammatory responses than the wild type (WT) virus in neonatal mice. Through in vitro characterization, we discover a mutant virus with a lysine to arginine substitution at position 101 of capsid (C) protein (termed K101R) displays a larger plaque phenotype, and replicates more efficiently in various cell lines. We then utilize reverse genetic technology to generate recombinant ZIKVs incorporating these lineage-specific substitutions based on an infectious cDNA clone of Asian ZIKV. Herein, we identify a panel of amino acid substitutions that are unique to the African lineage of ZIKVs compared to the Asian lineage by phylogenetic analysis and sequence alignment. However, viral determinants and the underlying mechanisms of enhanced virulence phenotype remain largely unknown. ![]() Increasing evidence shows the African lineage Zika virus (ZIKV) displays a more severe neurovirulence compared to the Asian ZIKV. ![]()
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