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

PLoS Pathogens

Kevin Maringer¹  Randy A. Albrecht¹  Ana Fernandez-Sesma¹  Shashank Tripathi¹  Alesha Grant¹  Megan C. Schwarz¹  Jean K. Lim¹  Julia A. Brown¹  Adolfo García-Sastre¹  Matthew J. Evans¹  Ana M. Maestre²  Ignacio Mena²  Vinod R. M. T. Balasubramaniam²  Marion Sourisseau³  Florian Krammer³  Susana V. Bardina³ 

[1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America;Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America;The Graduate School of Biological Sciences at the Icahn School of Medicine at Mount Sinai, Microbiology Training Area, New York, New York, United States of America

关键词: Mouse models;    Zika virus;    Pathogenesis;    Animal models of infection;    Cytokines;    Central nervous system;    Mammalian genomics;    Immune response;   

DOI  :  10.1371/journal.ppat.1006258

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY