Abstract
Stable adherence to epithelial surfaces is required for colonization by diverse host-associated microbes. Successful attachment of pathogenic microbes to host cells via adhesin molecules is also the first step in many devastating infections. Despite the primacy of epithelial adherence in establishing host-microbe associations, the evolutionary processes that shape this crucial interface remain enigmatic. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) encompass a multifunctional family of vertebrate cell surface proteins which are recurrent targets of bacterial adhesins at epithelial barriers. Here, we show that multiple members of the primate CEACAM family exhibit evidence of repeated natural selection at protein surfaces targeted by bacteria, consistent with pathogen-driven evolution. Divergence of CEACAM proteins between even closely related great apes is sufficient to control molecular interactions with a range of bacterial adhesins. Phylogenetic analyses further reveal that repeated gene conversion of CEACAM extracellular domains during primate divergence plays a key role in limiting bacterial adhesin host tropism. Moreover, we demonstrate that gene conversion has continued to shape CEACAM diversity within human populations, with abundant human CEACAM1 variants mediating evasion of adhesins from pathogenic Neisseria. Together this work reveals a mechanism by which gene conversion shapes first contact between microbes and animal hosts.
Highlights
Epithelial surfaces are typically the initial point of contact between metazoans and microbes (Brown and Clarke, 2017)
Our investigation of species-specific bacterial adherence to CEACAM1 revealed an unforeseen example of extreme genetic divergence within the great apes
The bonobo CEACAM1 gene could represent a rapid succession of single residue changes combined with multiple recombination events arising in bonobos under strong selection and/or a population bottleneck
Summary
Epithelial surfaces are typically the initial point of contact between metazoans and microbes (Brown and Clarke, 2017). Microbial adherence can trigger epithelial cell signaling cascades, further shaping host responses to resident and invasive microbes. Despite the fundamental importance of epithelial adherence for bacterial colonization and infectious disease pathogenesis, the dynamics of these interactions between host surface proteins and bacterial adhesions over evolutionary timescales remain a mystery. Theory predicts that exploitation of host proteins by pathogens places a significant burden on host populations, driving selection for beneficial mutations that limit microbial invasion or virulence. Epithelial surface proteins are essential for interacting with the environment and serve crucial cellular and physiological functions including barrier maintenance, cellcell communication, as well as coordinating host physiological and developmental pathways (Kuespert et al, 2006). The HEK293T cell line used in this study was obtained from ATCC which authenticated and screened the line for mycoplasma prior to shipping
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