title: Generalized selection to overcome innate immunity selects for host breadth in an RNA virus.
abstract: Virus-host coevolution has selected for generalized host defense against viruses, exemplified by interferon production/signaling and other innate immune function in eukaryotes such as humans. Although cell-surface binding primarily limits virus infection success, generalized adaptation to counteract innate immunity across disparate hosts may contribute to RNA virus emergence potential. We examined this idea using vesicular stomatitis virus (VSV) populations previously evolved on strictly immune-deficient (HeLa) cells, strictly immune competent (MDCK) cells, or on alternating deficient/competent cells. By measuring viral fitness in unselected human cancer cells of differing innate immunity, we confirmed that HeLa-adapted populations were specialized for innate immune-deficient hosts, whereas MDCK-adapted populations were relatively more generalized for fitness on hosts of differing innate immune capacity and of different species origin. We also confirmed that HeLa-evolved populations maintained fitness in immune-deficient nonhuman primate cells. These results suggest that innate immunity is more prominent than host species in determining viral fitness at the host-cell level. Finally, our prediction was inexact that selection on alternating deficient/competent hosts should produce innate viral generalists. Rather, fitness differences among alternating host-evolved VSV populations indicated variable capacities to evade innate immunity. Our results suggest that the evolutionary history of innate immune selection can affect whether RNA viruses evolve greater host-breadth.
authors.affiliation: Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut, 06520.|Current Address: Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, 14583.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wasik
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut, 06520.
authors.forename: Andrés R
authors.initials: AR
authors.lastname: Muñoz-Rojas
authors.affiliation: Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut, 06520.|Yale Institute for Biospheric Studies, Yale University, New Haven, Connecticut, 06511.
authors.forename: Kenichi W
authors.initials: KW
authors.lastname: Okamoto
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut, 06520. kathryn.miller-jensen@yale.edu.|Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, 06511. kathryn.miller-jensen@yale.edu.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Miller-Jensen
authors.affiliation: Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut, 06520. paul.turner@yale.edu.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Turner
mesh_terms: D000818:Animals; D004285:Dogs; D019143:Evolution, Molecular; D006367:HeLa Cells; D058507:Host Specificity; D006801:Humans; D007113:Immunity, Innate; D061985:Madin Darby Canine Kidney Cells; D012641:Selection, Genetic; D018116:Vesiculovirus / Q000235:genetics*
keywords: Emergence; experimental evolution; generalism; host range; interferon