Oral Presentation 9th Australasian Virology Society Meeting 2017

Zika virus attenuates the host innate response to infection (#55)

Kylie Van der Hoek 1 , Byron Shue 1 , Nicholas S Eyre 1 , Yulee khantistthiporn 1 , Jillian M Carr 2 , Matthew Gartner 1 , Lachlan A Jolly 3 , Tanja Jankovic-Karasoulos 3 , Claire T Roberts 3 , Karla J Helbig 4 , Michael R Beard 1
  1. Research Centre for Infectious Diseases, The University of Adelaide, Adelaide, SA, Australia
  2. Microbiology and Infectious Diseases, School of Medicine, Flinders University, Bedford Park, SA, Australia
  3. Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
  4. Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, Vic, Australia

Zika virus (ZIKV) is a flaviviridae family member that can readily cross the placenta causing placental insufficiency, spontaneous abortion and microcephaly in newborns. We set out to examine the early innate response of biologically relevant cells of neural (murine progenitor) and placental origin (HTR8, JEG3), to ZIKV (MR766, PRVABC59) infection. We found a significant impairment of IFN-beta and downstream ISG mRNA expression, despite evidence of robust viral replication. Moreover, ZIKV could significantly attenuate ISG mRNA expression and ISRE promoter activity in response to dsRNA (polyI:C) suggesting that ZIKV can actively reduce RIG-I sensing of ZIKV RNA and downstream ISG expression. Notably, mRNA expression of the antiviral ISG viperin, was significantly attenuated in all of the cell lines investigated. Exogenous expression of viperin in cultured cells resulted in significant impairment of ZIKV replication as determined by immunofluorescence microscopy and quantification of released virus by plaque assay. MEFs derived from viperin-/- CRISPR mice replicated ZIKV to higher titers (≈60% infection) compared to MEFs from viperin WT littermates (≈16%). To further understand infection and host response in the placenta we developed first trimester placental explant cultures and isolated primary trophoblasts. First trimester explants were positive for ZIKV RNA 96hs post infection while isolated cytotrophoblasts were also permissive for ZIKV infection as determined by qRT-PCR and IF analysis respectively. Collectively these results suggest that ZIKV has the capacity to attenuate host ISG expression allowing the virus to replicate unchecked Furthermore one of these ISGs, viperin has significant anti-ZIKV activity. Ongoing experiments will examine innate responses to ZKV infection in isolated primary trophoblasts and placental explant tissues cultures. Understanding how ZIKV perturbs the innate response in placental tissues and the cell types infected will aid in our understanding of ZIKV biology, pathogenesis and possible design of novel antiviral strategies.