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A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune responses

Tripathi, S, Balasubramaniam, V, Brown, JA, Mena, I, Grant, A, Bardina, SV, Maringer, Kevin, Schwarz, MC, Maestre, AM, Sourisseau, M , Albrecht, RA, Krammer, F, Evans, MJ, Fernandez-Sesma, A, Lim, JK and García-Sastre, A (2017) A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune responses PLoS Pathogens, 13 (3), e1006258. pp. 1-19.

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Abstract

Zika virus (ZIKV) is a mosquito borne flavivirus, which was a neglected tropical pathogen until it emerged and spread across the Pacific Area and the Americas, causing large human outbreaks associated with fetal abnormalities and neurological disease in adults. The factors that contributed to the emergence, spread and change in pathogenesis of ZIKV are not understood. We previously reported that ZIKV evades cellular antiviral responses by targeting STAT2 for degradation in human cells. In this study, we demonstrate that Stat2-/- mice are highly susceptible to ZIKV infection, recapitulate virus spread to the central nervous system (CNS), gonads and other visceral organs, and display neurological symptoms. Further, we exploit this model to compare ZIKV pathogenesis caused by a panel of ZIKV strains of a range of spatiotemporal history of isolation and representing African and Asian lineages. We observed that African ZIKV strains induce short episodes of severe neurological symptoms followed by lethality. In comparison, Asian strains manifest prolonged signs of neuronal malfunctions, occasionally causing death of the Stat2-/- mice. African ZIKV strains induced higher levels of inflammatory cytokines and markers associated with cellular infiltration in the infected brain in mice, which may explain exacerbated pathogenesis in comparison to those of the Asian lineage. Interestingly, viral RNA levels in different organs did not correlate with the pathogenicity of the different strains. Taken together, we have established a new murine model that supports ZIKV infection and demonstrate its utility in highlighting intrinsic differences in the inflammatory response induced by different ZIKV strains leading to severity of disease. This study paves the way for the future interrogation of strain-specific changes in the ZIKV genome and their contribution to viral pathogenesis.

Item Type: Article
Subjects : Biosciences and Medicine
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Tripathi, SUNSPECIFIEDUNSPECIFIED
Balasubramaniam, VUNSPECIFIEDUNSPECIFIED
Brown, JAUNSPECIFIEDUNSPECIFIED
Mena, IUNSPECIFIEDUNSPECIFIED
Grant, AUNSPECIFIEDUNSPECIFIED
Bardina, SVUNSPECIFIEDUNSPECIFIED
Maringer, Kevink.maringer@surrey.ac.ukUNSPECIFIED
Schwarz, MCUNSPECIFIEDUNSPECIFIED
Maestre, AMUNSPECIFIEDUNSPECIFIED
Sourisseau, MUNSPECIFIEDUNSPECIFIED
Albrecht, RAUNSPECIFIEDUNSPECIFIED
Krammer, FUNSPECIFIEDUNSPECIFIED
Evans, MJUNSPECIFIEDUNSPECIFIED
Fernandez-Sesma, AUNSPECIFIEDUNSPECIFIED
Lim, JKUNSPECIFIEDUNSPECIFIED
García-Sastre, AUNSPECIFIEDUNSPECIFIED
Date : 9 March 2017
Identification Number : 10.1371/journal.ppat.1006258
Copyright Disclaimer : Copyright 2017 Tripathi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 01 Mar 2017 12:34
Last Modified : 06 Jul 2017 06:58
URI: http://epubs.surrey.ac.uk/id/eprint/813653

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