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

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.

Zika Virus Encoding Nonglycosylated Envelope Protein Is Attenuated and Defective in Neuroinvasion

“…Several mouse models have been established to study ZIKV pathogenesis in immunocompetent, as well as immunodeficient, animals (for a review, see reference 33). Immunodeficient mice lacking the type I interferon (IFN) signaling pathways are highly susceptible to ZIKV infection (34)(35)(36)(37)(38)(39). A129 mice genetically lacking the IFN-␣/␤ receptor undergo significant body weight loss, show clinical disease with limb paralysis, and succumb to infection.…”

Zika Virus Infection: Induction, Restriction and Evasion of Host Interferon Responses

“…The recent emergence of ZIKV is multifactorial and likely includes the expanded geographical range of Aedes sp. mosquitoes, the immunological naivety of human populations outside of historically endemic regions and global travel of infected individuals [2]. In addition to these epidemiological consequences of globalization, ZIKV has evolved novel mechanisms to induce disease pathogenesis and evade host immune responses [1,2].…”

“…Importantly, although the commonly used immunocompro- Editorial mised murine models provide a useful tool to study viral pathogenesis, immunocompetent models will be important for examination of the host immune response [1,17]. In addition to cell-type-specific differences, recent evidence suggests that there may be strain-specific differences in ISG induction between contemporary and historical ZIKV isolates in both primary human astrocytes and in mouse models of pathogenesis [2,18]. However, it remains to be seen whether these strain-specific differences serve to increase the pathogenicity of the virus.…”

“…mosquitoes, the immunological naivety of human populations outside of historically endemic regions and global travel of infected individuals [2]. In addition to these epidemiological consequences of globalization, ZIKV has evolved novel mechanisms to induce disease pathogenesis and evade host immune responses [1,2]. Understanding how recently acquired viral polymorphisms influence viral pathogenesis and the host immune response during infection is crucial to further our understanding of ZIKV infection and pathogenesis.…”

“…The structural proteins form the virion particle are the primary targets for the host humoral immune response [1,2]. The multifunctional nonstructural proteins have been implicated in polyprotein processing, viral RNA replication, virion assembly, as well as evasion of the innate immune response [1].…”