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.

They are what you eat: Shaping of viral populations through nutrition and consequences for virulence

“…In our studies with influenza virus, we linked the emergence of a more diverse and virulent viral population with blunted interferon responses in obese hosts. Interferon treatment of obese mice restricted the emergence of a diverse quasispecies and attenuated the virulence of the resulting viral population, strengthening the claim that a robust innate immune response restricts subsequent infection severity, possibly through reduced viral replication and acquisition of a genetically diverse viral population [8,20,41]. Dietary metabolites also influence cellular metabolism and can push the body to a state of metainflammation; this prooxidant environment may also directly influence the genetic composition of the viral population [45].…”

The interplay between host community structure and pathogen life‐history constraints in driving the evolution of host‐range shifts

“…System‐specific modelling and experimental research into how host ecology and pathogen pleiotropy affect host‐range evolution in microcosms such as bacteria–bacteriophage systems will likely have important implications in understanding the structure and composition of microbiome communities (e.g., Manrique et al., ). Connecting our model to experimental work in eukaryotic viruses can also provide a more mechanistic understanding of the prerequisites for host stability in medically important viruses, such as vesicular stomatitis virus (e.g., Wasik, Muñoz‐Rojas, Okamoto, Miller‐Jensen, & Turner, ) which is used in oncolytic and anti‐HIV therapy (Lichty, Power, Stojdl, & Bell, ) as well as in live vaccine development (e.g., Regules et al., ). We highlight both comparative and experimental tests of our model as fruitful directions towards elucidating broader patterns of host‐range shifts.…”

Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells

“…RT-qPCR was performed as previously described 44 . Briefly, RNA was extracted using the RNEasy Mini Kit (Qiagen).…”