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

Humans encounter a diverse array of STa peptides during infection with different bacterial pathogens. These commonly include toxin variants STp and STh encoded by strains of Enterotoxigenic E. coli 10 . Pathogenic strains from other bacterial genera, including Yersinia and Vibrio species, also encode distinct STa variants 11, 12 . These peptides show considerable sequence variation in contrast to the endogenous GC-C ligands guanylin and uroguanylin that are nearly identical among primates ( Figure 1A , S1). To further examine how GC-C evolution in primates might be influenced by toxin interactions, we mapped rapidly evolving codons with significantly elevated dN/dS ratios to the primary structure of GC-C. Strikingly, all six positively-selected sites mapped to the extracellular ligand-binding domain of GC-C, whereas the intracellular domain is highly conserved ( Figure 1B, Table S3 ). These patterns of diversification of both STa and the GC-C ligandbinding domain support a model of recurring conflicts between diarrhea-causing bacteria and hosts over control of water secretion in the intestine.