Structural evolution of an immune evasion determinant shapes pathogen host tropism

• DOI: 10.1073/pnas.2301549120
• Publication Date: 2023-06-26T19:09:49Z
• Authors: Ashley L. Marcink...; Kalvis Brangulis; Alan P. Dupuis; Thomas M. Hart; Maxime Zamba‐Campero; Tristan A. Nowak; Jessica L. Stout; Inara Akopjana; Andris Kazaks; Janis Bogans; Alexander T. Ciota; Peter Kraiczy; Sergios-Orestis K...; Yi-Pin Lin
• Keywords: Evasion (ethics); Tissue tropism; Immune escape

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