Mechanisms of Emerging RNA Virus Adaptation to Hosts

Abstract

Emerging RNA viruses cause acute and chronic diseases that threaten the livelihoods of people in regions where the virus is endemic. As factors such as climate change and increased globalization, travel, and trade alter the co-occurrence of humans and reservoirs or vectors, opportunities for viral geographic expansion or viral spillover increase. Viral adaptation enabling intra- or interspecies transmission can cause outbreaks on the scale of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the coronavirus disease 2019 pandemic. Understanding the mechanisms by which emerging RNA viruses adapt to hosts can inform public health strategies targeting the appropriate vectors and reservoirs of the virus or the design of effective therapeutics. Therefore, we sought to identify the viral genetic determinants of host adaptation of two contrasting viruses, Mayaro virus (MAYV) and SARS-CoV-2. We used either selective sweep detection methods or experimental evolution to identify viral mutations with putative adaptive potential. A selective sweep region was identified in the Spike gene of human SARS-CoV-2 sequences. A residue at site 519 in this region of Spike was identified that differed from that of closely related sarbecoviruses infecting bats and pangolins. The ancestral mutation H519N reduced the entry of pseudotyped viruses in human ACE2 (hACE2)-expressing cells and decreased replication in human lung cells through reduced hACE2 binding. Next, serial passaging of SARS-CoV-2 in cells expressing the animal ACE2 receptor identified the recurring mutation A222V in the Spike gene. Spike A222V enhanced replication of SARS-CoV-2 in primary white-tailed deer lung cells through an ACE2-independent mechanism. Lastly, serial passaging of MAYV in cells from two urban mosquito vectors, Aedes aegypti and Aedes albopictus, identified a mutation in E2, T179N, that increased viral fitness in these cells. E2-T179N increased the transmission efficiency of MAYV by Aedes aegypti while coming at the cost of reduced fitness and virulence in mice. Taken together, these works highlight the impact of single mutations on virus fitness within and between hosts. Our findings underscore the importance of combining surveillance, limiting specific reservoir and vector exposure, and therapeutic design targeting adaptive residues to prevent the further evolution and emergence of SARS-CoV-2 and MAYV.