Abstract
The Zika virus (ZIKV) was first isolated in Africa in 1947. It was shown to be a mild virus that had limited threat to humans. However, the resurgence of the ZIKV in the most recent Brazil outbreak surprised us because it causes severe human congenital and neurologic disorders including microcephaly in newborns and Guillain-Barré syndrome in adults. Studies showed that the epidemic ZIKV strains are phenotypically different from the historic strains, suggesting that the epidemic ZIKV has acquired mutations associated with the altered viral pathogenicity. However, what genetic changes are responsible for the changed viral pathogenicity remains largely unknown. One of our early studies suggested that the ZIKV structural proteins contribute in part to the observed virologic differences. The objectives of this study were to compare the historic African MR766 ZIKV strain with two epidemic Brazilian strains (BR15 and ICD) for their abilities to initiate viral infection and to confer neurocytopathic effects in the human brain’s SNB-19 glial cells, and further to determine which part of the ZIKV structural proteins are responsible for the observed differences. Our results show that the historic African (MR766) and epidemic Brazilian (BR15 and ICD) ZIKV strains are different in viral attachment to host neuronal cells, viral permissiveness and replication, as well as in the induction of cytopathic effects. The analysis of chimeric viruses, generated between the MR766 and BR15 molecular clones, suggests that the ZIKV E protein correlates with the viral attachment, and the C-prM region contributes to the permissiveness and ZIKV-induced cytopathic effects. The expression of adenoviruses, expressing prM and its processed protein products, shows that the prM protein and its cleaved Pr product, but not the mature M protein, induces apoptotic cell death in the SNB-19 cells. We found that the Pr region, which resides on the N-terminal side of prM protein, is responsible for prM-induced apoptotic cell death. Mutational analysis further identified four amino-acid residues that have an impact on the ability of prM to induce apoptosis. Together, the results of this study show that the difference of ZIKV-mediated viral pathogenicity, between the historic and epidemic strains, contributed in part the functions of the structural prM-E proteins.
Highlights
The 2015 Zika virus (ZIKV) outbreak in South America has a tremendous impact on public health.It was estimated that it left more than three thousand babies who were born with microcephaly, due to ZIKV infection in Brazil alone [1]
Potential virologic differences between the African and Asian ZIKV lineages could be elucidated by exchanging different components of the ZIKV genome between the two viral lineages by generating chimeric viruses. Through such analysis of chimeric viral infection, any virologic changes, due to the swapping alteration would allow us to correlate a virologic change with a specific domain or gene of the ZIKV genome. By using this strategy and comparative analysis of a historic African ZIKV MR766 strain and an epidemic Brazilian BR15 strain in human host cells, we discovered in our earlier study that the structural proteins of the BR15 and MR766 ZIKV strains differ in their ability to initiate viral infection [30]
A human brain glial cell line SNB-19 was used in this study because it is highly permissive to ZIKV infection [32]
Summary
The 2015 Zika virus (ZIKV) outbreak in South America has a tremendous impact on public health. It was estimated that it left more than three thousand babies who were born with microcephaly, due to ZIKV infection in Brazil alone [1]. Monitoring those babies after birth continue to show various developmental and neurologic disorders that are known as the congenital ZIKV syndrome [2,3]. In the most recent ZIKV outbreak, the virus spread to eighty-four countries, territories, or sub-national areas, with an estimate of over 1.5 million affected individuals [13]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have