Defensin-driven viral evolution

Enteric alpha-defensins are potent effectors of innate immunity that are abundantly expressed in the small intestine. Certain enteric bacteria and viruses are resistant to defensins and even appropriate them to enhance infection despite neutralization of closely related microbes. We therefore hypothesized that defensins impose selective pressure during fecal-oral transmission. Upon passaging a defensin-sensitive serotype of adenovirus in the presence of a human defensin, mutations in the major capsid protein hexon accumulated. In contrast, prior studies identified the vertex proteins as important determinants of defensin antiviral activity. Infection and biochemical assays suggest that a balance between increased cell binding and a downstream block in intracellular trafficking mediated by defensin interactions with all of the major capsid proteins dictates the outcome of infection. These results extensively revise our understanding of the interplay between defensins and non-enveloped viruses. Furthermore, they provide a feasible rationale for defensins shaping viral evolution, resulting in differences in infection phenotypes of closely related viruses. Author summary Defensins are potent antimicrobial peptides that are found on human mucosal surfaces and can directly neutralize viruses. They are abundant in the small intestine, which is constantly challenged by ingested viral pathogens. Interestingly, non-enveloped viruses, such as adenovirus, that infect the gastrointestinal system are unaffected by defensins or can even appropriate defensins to enhance their infection. In contrast, respiratory adenoviruses are neutralized by the same defensins. How enteric viruses overcome defensin neutralization is not well understood. Our studies are the first to show that defensins can drive the evolution of non-enveloped viruses. Furthermore, we identify important components within human adenovirus that dictate sensitivity to defensins. This new insight into defensin-virus interactions informs our understanding of mucosal immunity to viral infections.