Structural evolution of an immune evasion determinant shapes pathogen host tropism

• Published in: Proceedings of the National Academy of Sciences - PNAS 2023-07, Vol.120 (27), p.e2301549120-e2301549120
• Main Authors: Marcinkiewicz, Ashley L, Brangulis, Kalvis, Dupuis, 2nd, Alan P, Hart, Thomas M, Zamba-Campero, Maxime, Nowak, Tristan A, Stout, Jessica L, Akopjana, Inara, Kazaks, Andris, Bogans, Janis, Ciota, Alexander T, Kraiczy, Peter, Kolokotronis, Sergios-Orestis, Lin, Yi-Pin
• Format: Article
• Language: English
• Subjects: Age; Animals; Bacteria; Bacterial Proteins - metabolism; Binding; Biological Sciences; Birds; Borrelia burgdorferi; Complement; Complement factor H; Complement Factor H - genetics; Complement Factor H - metabolism; Complement inhibitors; Complement system; Complement System Proteins - genetics; Conserved sequence; Crystal structure; Human performance; Humans; Immune clearance; Immune evasion; Immune Evasion - genetics; Infectious diseases; Infectivity; Lyme disease; Lyme Disease - microbiology; Membrane Proteins - metabolism; Molecular modelling; Pathogens; Phenotypes; Phylogeny; Proteins; Rodents; Tropism; Vector-borne diseases; Vertebrates; Viral Tropism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2301549120

Modern infectious disease outbreaks often involve changes in host tropism, the preferential adaptation of pathogens to specific hosts. The Lyme disease-causing bacterium ( ) is an ideal model to investigate the molecular mechanisms of host tropism, because different variants of these tick-transmitted bacteria are distinctly maintained in rodents or bird reservoir hosts. To survive in hosts and escape complement-mediated immune clearance, 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 protein 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 mechanisms 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.