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

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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.

          Author summary

          Zika virus is the most recent viral pathogen to cause a global public health emergency. It is distinct from other flaviviruses in its ability to cause transplacental infection, fetal abnormalities and vector independent transmission through body fluids in humans. Over the last year, there has been rapid progress in the development of animal models, which can be used to study ZIKV pathogenesis. In this study, we demonstrate for the first time that Stat2 -/- mice are highly susceptible to ZIKV infection and recapitulate aspects of ZIKV pathogenesis and disease. We use this model to delineate whether strain specific differences in ZIKV pathogenesis exist, using diverse strains representing both African and Asian lineages. We show that African strains in general are more virulent than Asian strains and their pathogenicity associates closely with the degree of inflammatory immune response in the CNS of infected mice, and does not necessarily correlate with viral RNA levels. Thus, we establish Stat2 -/- mice as new model to study ZIKV pathogenesis and use it to characterize inherent differences in the virulence among ZIKV strains. More importantly, we also highlight a potential role of the host inflammatory immune response in mediating differential pathogenesis among ZIKV strains.

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          Most cited references 20

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          Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection.

          Zika virus (ZIKV) can be transmitted sexually between humans. However, it is unknown whether ZIKV replicates in the vagina and impacts the unborn fetus. Here, we establish a mouse model of vaginal ZIKV infection and demonstrate that, unlike other routes, ZIKV replicates within the genital mucosa even in wild-type (WT) mice. Mice lacking RNA sensors or transcription factors IRF3 and IRF7 resulted in higher levels of local viral replication. Furthermore, mice lacking the type I interferon (IFN) receptor (IFNAR) became viremic and died of infection after a high-dose vaginal ZIKV challenge. Notably, vaginal infection of pregnant dams during early pregnancy led to fetal growth restriction and infection of the fetal brain in WT mice. This was exacerbated in mice deficient in IFN pathways, leading to abortion. Our study highlights the vaginal tract as a highly susceptible site of ZIKV replication and illustrates the dire disease consequences during pregnancy.
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            Zika virus. II. Pathogenicity and physical properties.

             G S Dick (1952)
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              Characterization of Lethal Zika Virus Infection in AG129 Mice

              Background Mosquito-borne Zika virus (ZIKV) typically causes a mild and self-limiting illness known as Zika fever, which often is accompanied by maculopapular rash, headache, and myalgia. During the current outbreak in South America, ZIKV infection during pregnancy has been hypothesized to cause microcephaly and other diseases. The detection of ZIKV in fetal brain tissue supports this hypothesis. Because human infections with ZIKV historically have remained sporadic and, until recently, have been limited to small-scale epidemics, neither the disease caused by ZIKV nor the molecular determinants of virulence and/or pathogenicity have been well characterized. Here, we describe a small animal model for wild-type ZIKV of the Asian lineage. Methodology/Principal Findings Using mice deficient in interferon α/β and Ɣ receptors (AG129 mice), we report that these animals were highly susceptible to ZIKV infection and disease, succumbing within seven to eight days. Rapid viremic dissemination was observed in visceral organs and brain; but only was associated with severe pathologies in the brain and muscle. Finally, these results were consistent across challenge routes, age of mice, and inoculum doses. These data represent a mouse model for ZIKV that is not dependent on adapting ZIKV to intracerebral passage in mice. Conclusions/Significance Foot pad injection of AG129 mice with ZIKV represents a biologically relevant model for studying ZIKV infection and disease development following wild-type virus inoculation without the requirement for adaptation of the virus or intracerebral delivery of the virus. This newly developed Zika disease model can be exploited to identify determinants of ZIKV virulence and reveal molecular mechanisms that control the virus-host interaction, providing a framework for rational design of acute phase therapeutics and for vaccine efficacy testing.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                9 March 2017
                March 2017
                : 13
                : 3
                Affiliations
                [1 ]Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                [2 ]Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                [3 ]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
                [4 ]Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
                NIH, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                • Conceptualization: AGS ST FK.

                • Data curation: ST VRMTB JAB IM.

                • Formal analysis: ST JAB IM.

                • Funding acquisition: AGS AFS.

                • Investigation: ST VRMTB JAB IM RAA MCS.

                • Methodology: ST IM.

                • Project administration: ST AGS.

                • Resources: AGS AFS JKL SVB MS KM AMM AG.

                • Software: ST JAB.

                • Supervision: AGS.

                • Validation: ST.

                • Visualization: ST IM.

                • Writing – original draft: ST.

                • Writing – review & editing: AGS JKL FK MJE IM.

                [¤]

                Current address: University of Surrey, Surrey, United Kingdom

                Article
                PPATHOGENS-D-16-02834
                10.1371/journal.ppat.1006258
                5373643
                28278235
                © 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.

                Page count
                Figures: 5, Tables: 0, Pages: 19
                Product
                Funding
                This work was partially funded by a supplement to NIAID grant U19AI118610 as part of the HIPC (AGS) and by R01AI073450 (AFS). KM was funded by a Sir Henry Wellcome Trust Fellowship (096062). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                2017-03-30
                All relevant data are within the paper and its Supporting Information files.

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