Structural evolution of an immune evasion determinant shapes pathogen host tropism

Modern infectious disease outbreaks often involve changes in host tropism, the prefer-ential adaptation of pathogens to specific hosts. The Lyme disease-causing bacterium Borrelia burgdorferi (Bb) is an ideal model to investigate the molecular mechanisms of host tropism, because different variants of these tick-transmitted bacteria are dis-tinctly maintained in rodents or bird reservoir hosts. To survive in hosts and escape complement-mediated immune clearance, Bb produces the outer surface protein CspZ that binds the complement inhibitor factor H (FH) to facilitate bacterial dissemination in vertebrates. Despite high sequence conservation, CspZ variants differ in human FH-binding ability. Together with the FH polymorphisms between vertebrate hosts, these findings suggest that minor sequence variation in this bacterial outer surface pro-tein may confer dramatic differences in host-specific, FH- binding-mediated infectivity. We tested this hypothesis by determining the crystal structure of the CspZ-human FH complex, and identifying minor variation localized in the FH-binding interface yielding bird and rodent FH-specific binding activity that impacts infectivity. Swapping the divergent region in the FH-binding interface between rodent-and bird-associated CspZ variants alters the ability to promote rodent-and bird-specific early -onset dissemination. We further linked these loops and respective host-specific, complement-dependent phenotypes with distinct CspZ phylogenetic lineages, elucidating evolutionary mech-anisms driving host tropism emergence. Our multidisciplinary work provides a novel molecular basis for how a single, short protein motif could greatly modulate pathogen host tropism.

Automated summary

Modern infectious disease outbreaks often involve changes in host tropism. The Lyme disease-causing bacterium Bb is an ideal model to investigate the molecular mechanisms of host tropism. Our research shows that minor sequence variation in the bacterial outer surface protein CspZ may confer dramatic differences in host-specific infectivity. We also identified the evolutionary mechanisms driving host tropism emergence.