Zika virus (ZIKV) belongs to a positive single-strand flavivirus family that has recently emerging pathogens, West Nile virus (WNV), chikungunya virus (CHKV), and dengue virus (DENV). It is spread by the Aedes mosquito and any cases of ZIKV infection are asymptomatic and the most common symptoms of infection are rash, fever, and joint pain. However, a number of epidemiology data strongly indicate that newborns of mothers who had ZIKV infection during pregnancy are at an increased risk for microcephaly. Recent animal studies also showed that IFNAR knockout (KO) mice were highly susceptible for ZIKV infection and developed neurological diseases. Furthermore, previous studies of mice infected intraperitoneally showed the brain tropism of ZIKV infection where the virus infected both neurons and glia, producing a variety of intracytoplasmic viral factories, likely referred to what we now know as ?autophagosomes?. Indeed, ZIKV infection of fibroblasts also associates with the formation of numerous double-membrane autophagosomes. DENV, closely related to ZKIV, also induces an activation of autophagy for its replication, indicating that both ZIKV and DENV increase their replication via the robust induction of autophagy in the host cells. Thus, the primary goal of this study is to investigate how ZIKV induces host?s autophagy for its viral lifecycle. Our preliminary study has discovered a novel ZIKV-mediated induction of autophagy pathway. Specifically, the ZIKV NS4A and NS4B serve as pro-autophagy molecules via their suppression of Akt kinase activity, which increases autophagy and thereby enhances viral replication. Thus, we will study the specific mechanisms of how the ZIKV NS4A and NS4B cooperate to induce autophagy for viral replication (Aim 1) and test whether the increase of autophagy is necessary for efficient in vitro and in vivo ZIKV replication and disease induction (Aim 2). The successful outcome of this study should considerably impact our understanding how ZIKV subverts the autophagic machinery to benefit its replication.
Newborns of mothers who had Zika virus (ZIKV) infection during pregnancy are at an increased risk for microcephaly Furthermore, ZIKV infection is associated with a significant incidence of neurological symptoms, including Guillain-Barre syndrome. ZIKV robustly increase their replication via the induction of autophagy in the host cells. Thus, the primary goal of this study is to investigate the role of autophagy for ZIKV infection and neurological disease induction.
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| Foo, Suan-Sin; Chen, Weiqiang; Chan, Yen et al. (2017) Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy. Nat Microbiol 2:1558-1570 |
| Li, Chunfeng; Zhu, Xingliang; Ji, Xue et al. (2017) Chloroquine, a FDA-approved Drug, Prevents Zika Virus Infection and its Associated Congenital Microcephaly in Mice. EBioMedicine 24:189-194 |
