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Evaluation of Zika Virus-specific T-cell Responses in Immunoprivileged Organs of Infected Ifnar1-/- Mice
Published on: October 17, 2018
A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune
Shashank Tripathi1,2, Vinod R M T Balasubramaniam1,2, Julia A Brown1,3
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
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.
Insights
A new Stat2-/- mouse model shows susceptibility to Zika virus (ZIKV) infection. African ZIKV strains cause severe neurological symptoms and higher inflammation compared to Asian strains.
Area of Science:
- Virology
- Immunology
- Neuroscience
Background:
- Zika virus (ZIKV) emerged as a significant public health threat, causing neurological disease and fetal abnormalities.
- The mechanisms behind ZIKV's emergence, spread, and altered pathogenesis remain unclear.
- ZIKV evades host antiviral responses by targeting STAT2 for degradation.
Purpose of the Study:
- To establish a mouse model for ZIKV infection and pathogenesis.
- To compare the pathogenesis of different ZIKV strains (African vs. Asian) in vivo.
- To investigate the role of STAT2 in ZIKV susceptibility and disease severity.
Main Methods:
- Generation and characterization of Stat2-/- mice for ZIKV susceptibility.
- Infection of Stat2-/- mice with diverse ZIKV strains (African and Asian lineages).
- Assessment of viral spread, neurological symptoms, organ pathology, and inflammatory responses.
Main Results:
- Stat2-/- mice are highly susceptible to ZIKV, exhibiting CNS and visceral organ infection and neurological symptoms.
- African ZIKV strains induced more severe neurological symptoms, higher lethality, and increased brain inflammation compared to Asian strains.
- Viral RNA levels did not correlate with observed pathogenicity, suggesting other factors influence disease severity.
Conclusions:
- A novel Stat2-/- mouse model effectively recapitulates ZIKV infection and pathogenesis.
- Intrinsic differences in inflammatory responses to African and Asian ZIKV strains contribute to varying disease severity.
- This model facilitates future research into ZIKV strain-specific genomic changes and their impact on pathogenesis.
