Dual Host-Virus Arms Races Shape an Essential Housekeeping Protein

Abstract

Author SummaryGenetic differences between mammalian species dictate the patterns of viral infection observed in nature. They also define how viruses must evolve in order to infect new mammalian hosts, giving rise to new and sometimes pandemic diseases. Because viruses must enter cells before they can replicate, new diseases often emerge when existing viruses evolve the ability to bind to the cell-surface receptor of a new species. At the same time, host cell receptors also evolve to counteract virus attacks. This back-and-forth evolution between virus and host can lead to an arms race that shapes the sequences of the proteins involved. In wild rodent populations, the retrovirus MMTV and New World arenaviruses both exploit Transferrin Receptor 1 (TfR1) to enter the cells of their hosts. Here we show that the physical interactions between these viruses and TfR1 have triggered evolutionary arms race dynamics that have directly modified the sequence of TfR1 and at least one of the viruses involved. Computational evolutionary analysis allowed us to identify specific residues in TfR1 that define patterns of viral infection in nature. The approach presented here can theoretically be applied to the study of any virus, through analysis of host genes known to be key to controlling viral infection. As such, this approach can expand our understanding of how viruses emerge from wildlife reservoirs, and how they drive the evolution of host genes.