Interplay between Zika virus and host type I interferon mediated immune response

Abstract

Zika virus (ZIKV) is a single-stranded, positive-sense RNA virus that is mainly transmitted by mosquito biting. ZIKV belongs to the family Flaviviridae , genus Flavivirus , which includes other important human pathogens including dengue virus, yellow fever virus, West Nile virus, and Japanese encephalitis virus. ZIKV was first isolated from a sentinel rhesus monkey in the Zika forest of Uganda in 1947. Following the outbreak of ZIKV in Yap Island of Micronesia in 2007 and the largest Zika pandemic in Brazil in 2015, ZIKV has rapidly spread through the Pacific islands and the Americas, resulting in an estimated two million infections per year. Due to its unexpected causal link to microcephaly in fetus and Guillain-Barre syndrome in adults, the current ongoing ZIKV epidemic was declared as a public health emergency of international concern by the World Health Organization in February, 2016. Accumulated evidence has demonstrated that ZIKV preferentially targets human neuronal progenitor cells, disrupts proliferation and differentiation, and triggers a strong immune response, resulting in significant neuronal cell death and microcephaly phenotype. Currently, no vaccines or specific antiviral drugs are available to prevent or treat ZIKV infections. Upon ZIKV infection, host cells immediately initiate several lines of antiviral innate immune responses, including the production of type I interferon (IFN) and its downstream signaling pathways. Type I IFN response is well evidenced to play a critical role during ZIKV infection, and mice deficient in type I IFN receptor are highly susceptible to ZIKV infection upon various injection routes. Type I IFN and its downstream signaling molecules (e.g. IFITM1 and IFITM3) show significant anti-ZIKV effects in both cell culture and animal models. Meanwhile, ZIKV has evolved diverse strategies to antagonize the host defense system through blocking the production of type I IFN and its downstream signaling, or escaping from antiviral effects of individual ISGs. Like other mosquito-borne flaviviruses, the viral proteins NS2B, NS3, NS4B and NS5, as well as the subgenomic flavivirus RNA (sfRNA), have been identified as potent suppressors of type I IFN induction and its effector pathways. Especially, ZIKV NS5 directly binds to STAT2, and leads to the proteasomal degradation of STAT2, resulting in the silencing of type I IFN signaling. These remarkable achievements in recent two years not only lead to the better understanding of ZIKV infection and pathogenesis, but also provide useful clues for the development of antiviral drugs and vaccine candidates. Several ISGs and their enzymatic products, including 25-Hydroxycholesterol, have been well characterized with potent anti-ZIKV activity. A few recombinant live-attenuated ZIKV vaccine candidates have been rationally constructed via reverse genetics with increased IFN sensitivity, which attributed to the attenuation phenotype in immunocompetent animals. Here, we summarize recent advances in the interplay between ZIKV and host type I IFN-mediated immune response.