Pathogen-driven evolution of host cellular receptors

Viruses are obligate pathogens that must both evade host proteins to avoid detection as well as engage alternate host proteins to promote their replication. Hosts are obligated to maintain their fitness in the face of viral pressure, without compromising the homeostatic function of virally utilized proteins. Therefore, if there is a potentially adaptive mutation in a host population that will protect it from infection, it is likely to spread. As it increases in frequency, this threatens the virus, as its susceptible host population dwindles. A seesaw of reciprocal adaptation will leave its imprint on both host and virus. Cellular receptors, which function as the access point to the host cell for viruses, harbor the signature of the antagonistic dynamic described above in the form of recurrent positive selection. Here, I use evolutionary analysis to gather evidence for the current host reservoir of Ebola virus. Live virus has yet to be isolated from any individual species, therefore we looked for a signature of sustained adaptive evolution in the host cellular receptor, Niemann Pick C1 (NPC1). I find that compared to primate and rodent NPC1, bat NPC1 harbors an overall signature of recurrent positive natural selection. This suggests that bats are the long-term reservoir host of filoviruses, which include Ebola virus. In addition, we link a positively selected site in bat NPC1 to differences in Ebola viral entry. I also use evolutionary analysis to pinpoint the nature of immunodeficiency virus resistance in New World monkeys. New World monkeys lack immunodeficiency viruses, while the other two major clades of simians harbor diverse strains. I re-evaluated the evolution of primate CCR5, the co-receptor for HIV and SIVs, to find that indeed, the New World monkey clade of primates harbored a signature of diversifying selection in contrast to the two other clades (Old World monkeys and hominoids) where simian immunodeficiency viruses are found. I was able to characterize the nature of this resistance by identifying a single positively selected site that has a large affect on viral entry within CCR5’s N-terminus. This potent blockade may partially explain the lack of SIVs in New World monkeys.