Conflicts with diarrheal pathogens trigger rapid evolution of an intestinal signaling axis

Clayton M. Carey; Sarah E. Apple; Zoe A. Hilbert; Michael S. Kay; Nels C. Elde

Given functionally consequential variation in GC-C that impacts both enterotoxin and uroguanylin interactions, we propose a model of compensatory coevolution triggered by bacterial enterotoxin interactions ( Figure 4C ). In this model, mutations in GC-C that allow escape from overstimulation by STa can provide a fitness benefit even at the cost of disrupting the interaction with uroguanylin. This intermediate state of low affinity with endogenous peptides is tolerated while toxin susceptible variants are culled from the population, given that survival is possible when GC-C signaling is disrupted 23 . Subsequent compensatory mutations in uroguanylin that optimize signaling interactions with GC-C might then outcompete mismatched variants with compromised receptorligand interfaces. In this proposed scenario, a single pathogen encoded protein directly influences the evolution of the host receptor, which subsequently impacts variation in the endogenous ligand.