Gain without pain: adaptation and increased virulence of Zika virus in vertebrate host without fitness cost in mosquito vector

Author:

Jaeger Anna S.1,Marano Jeffrey2,Riemersma Kasen K.3,Castaneda David1,Pritchard Elise M.1,Pritchard Julia C.1,Bohm Ellie K.1,Baczenas John J.45,O'Connor Shelby L.45ORCID,Weger-Lucarelli James2ORCID,Friedrich Thomas C.35ORCID,Aliota Matthew T.1ORCID

Affiliation:

1. Department of Veterinary and Biomedical Sciences, University of Minnesota , Twin Cities, Minnesota, USA

2. Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University , Blacksburg, Virginia, USA

3. Department of Pathobiological Sciences, University of Wisconsin-Madison , Madison, Wisconsin, USA

4. Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison , Madison, Wisconsin, USA

5. Wisconsin National Primate Research Center, University of Wisconsin-Madison , Madison, Wisconsin, USA

Abstract

ABSTRACT Zika virus (ZIKV) is now in a post-pandemic period, for which the potential for re-emergence and future spread is unknown. Adding to this uncertainty is the unique capacity of ZIKV to directly transmit between humans via sexual transmission. Recently, we demonstrated that direct transmission of ZIKV between vertebrate hosts leads to rapid adaptation resulting in enhanced virulence in mice and the emergence of three amino acid substitutions (NS2A-A117V, NS2A-A117T, and NS4A-E19G) shared among all vertebrate-passaged lineages. Here, we further characterized these host-adapted viruses and found that vertebrate-passaged viruses do not lose fitness or transmission potential in mosquitoes. To understand the contribution of genetic changes to the enhanced virulence and transmission phenotype, we engineered these amino acid substitutions, singly and in combination, into a ZIKV infectious clone. We found that NS4A-E19G contributed to the enhanced virulence and mortality phenotype in mice. Further analyses revealed that NS4A-E19G results in increased viral loads and distinct transcriptional patterns for innate immune genes in the brain. None of the substitutions contributed to changes in mosquito vector competence. Together, these findings suggest that direct transmission chains could enable the emergence of more virulent ZIKV strains without compromising mosquito transmission capacity, although the underlying genetics of these adaptations are complex. IMPORTANCE Previously, we modeled direct transmission chains of Zika virus (ZIKV) by serially passaging ZIKV in mice and mosquitoes and found that direct mouse transmission chains selected for viruses with increased virulence in mice and the acquisition of non-synonymous amino acid substitutions. Here, we show that these same mouse-passaged viruses also maintain fitness and transmission capacity in mosquitoes. We used infectious clone-derived viruses to demonstrate that the substitution in nonstructural protein 4A contributes to increased virulence in mice.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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