| Description |
Free living organisms live in constant tension with infectious microbes. This conflict has long been appreciated as a driving force in the evolution of immunity in host organisms. While being a useful framework, the classic model of pathogen- driven evolution of continuously escalating host immune responses fails to capture the full complexity at this interface. In this dissertation, I use a variety of experimental approaches to understand how pathogens shape host evolution in two previously unexplored areas of study. First, I investigate how selective forces balance the protective benefits of immune defense pathways against their associated costs using the primate oligoadenylate synthetase 1 (OAS1) / Ribonuclease L (RNase L) pathway as a model system. OAS1 detects viral RNAs and activates RNase L to kill infected cells but can also be activated by host RNAs. After developing an assay in budding yeast to test the activity of OAS variants, I show that loss-of-function mutations in OAS1 that debilitate antiviral catalytic function are surprisingly common among primates. These results reveal how immune defenses that potentially damage the host itself can be forfeited, in contrast to more simple models of escalating genetic conflicts. Second, I investigate how evolution of host genes involved in physiological processes are shaped by interactions with pathogens. I focus on the intestinal heat-stable enterotoxin (STa) receptor Guanylate Cyclase-C (GC-C) as a model system. GC- C normally regulates water levels in the gut through interactions with endogenous guanylin peptides to promote water secretion. Hyperactivation of GC-C by infectious bacteria producing STa results in the dissemination of bacteria in watery diarrhea. Using phylogenetic analysis, I show that the GC-C toxin binding domain evolved under recurrent positive selection in several clades of mammals. I then use in vitro techniques and intestinal organoids to demonstrate how diversification of GC-C leads to species specific resistances and susceptibilities to STa across mammals, providing evidence for an ongoing evolutionary arms race between GC- C and bacterial pathogens. Together, these experiments extend studies of host- pathogen evolutionary conflict to essential physiological functions and demonstrate how costs confound the classic model of the continuously escalating arms race between pathogens and immune functions. |
