Maintenance of a host-specific minority mutation in the West Nile virus NS3

Haley S Caldwell; Lili Kuo; Janice D Pata; Alan P Dupuis 2nd; Jamie J Arnold; Calvin Yeager; Jessica Stout; Cheri A Koetzner; Anne F Payne; Sean M Bialosuknia; Elyse M Banker; Taylor A Nolen; Craig E Cameron; Alexander T Ciota

doi:10.1016/j.isci.2023.107468

Maintenance of a host-specific minority mutation in the West Nile virus NS3

iScience. 2023 Jul 26;26(8):107468. doi: 10.1016/j.isci.2023.107468. eCollection 2023 Aug 18.

Authors

Haley S Caldwell^{1

2}, Lili Kuo¹, Janice D Pata^{2

3}, Alan P Dupuis 2nd¹, Jamie J Arnold⁴, Calvin Yeager⁴, Jessica Stout¹, Cheri A Koetzner¹, Anne F Payne¹, Sean M Bialosuknia¹, Elyse M Banker¹, Taylor A Nolen¹, Craig E Cameron⁴, Alexander T Ciota^{1

2}

Affiliations

¹ The Arbovirus Laboratory, Wadsworth Center, New York State Department of Health, Slingerlands, NY 12159, USA.
² Department of Biomedical Sciences, State University of New York at Albany, School of Public Health, Rensselaer, NY 12144, USA.
³ Wadsworth Center, New York State Department of Health, Albany, NY 12208, USA.
⁴ Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.

Abstract

West Nile virus (WNV), the most prevalent arthropod-borne virus (arbovirus) in the United States, is maintained in a cycle between Culex spp. mosquitoes and birds. Arboviruses exist within hosts and vectors as a diverse set of closely related genotypes. In theory, this genetic diversity can facilitate adaptation to distinct environments during host cycling, yet host-specific fitness of minority genotypes has not been assessed. Utilizing WNV deep-sequencing data, we previously identified a naturally occurring, mosquito-biased substitution, NS3 P319L. Using both cell culture and experimental infection in natural hosts, we demonstrated that this substitution confers attenuation in vertebrate hosts and increased transmissibility by mosquitoes. Biochemical assays demonstrated temperature-sensitive ATPase activity consistent with host-specific phenotypes. Together these data confirm the maintenance of host-specific minority variants in arbovirus mutant swarms, suggest a unique role for NS3 in viral fitness, and demonstrate that intrahost sequence data can inform mechanisms of host-specific adaptation.

Keywords: Bioinformatics; Genetics; Virology.

Abstract

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