title: 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.
authors.affiliation: 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.
authors.forename: Shashank
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: 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.
authors.forename: Vinod R M T
authors.initials: VR
authors.lastname: Balasubramaniam
authors.affiliation: Department of Microbiology, 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.
authors.forename: Julia A
authors.identifier: 0000-0002-9172-069X
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Ignacio
authors.identifier: 0000-0001-5464-7086
authors.initials: I
authors.lastname: Mena
authors.affiliation: 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.
authors.forename: Alesha
authors.initials: A
authors.lastname: Grant
authors.affiliation: Department of Microbiology, 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.
authors.forename: Susana V
authors.identifier: 0000-0002-6776-2697
authors.initials: SV
authors.lastname: Bardina
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Kevin
authors.identifier: 0000-0003-0977-8807
authors.initials: K
authors.lastname: Maringer
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Megan C
authors.identifier: 0000-0001-8715-2039
authors.initials: MC
authors.lastname: Schwarz
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Maestre
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Marion
authors.initials: M
authors.lastname: Sourisseau
authors.affiliation: 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.
authors.forename: Randy A
authors.identifier: 0000-0003-4008-503X
authors.initials: RA
authors.lastname: Albrecht
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Florian
authors.initials: F
authors.lastname: Krammer
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Matthew J
authors.identifier: 0000-0002-4991-3877
authors.initials: MJ
authors.lastname: Evans
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Jean K
authors.initials: JK
authors.lastname: Lim
authors.affiliation: 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.|Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Adolfo
authors.identifier: 0000-0002-6551-1827
authors.initials: A
authors.lastname: García-Sastre
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007249:Inflammation / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010802:Phylogeny; D060888:Real-Time Polymerase Chain Reaction; D000071244:Zika Virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D000071243:Zika Virus Infection / Q000276:immunology*