Structural evolution of an immune evasion determinant shapes pathogen host tropism

Ashley L Marcinkiewicz, Kalvis Brangulis (Coresponding Author), 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 Kolokotronis (Coresponding Author), Yi-Pin Lin (Coresponding Author)

Research output: Contribution to journalArticlepeer-review


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 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, 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 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.

Original languageEnglish
Article numbere2301549120
Pages (from-to)e2301549120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number27
Publication statusPublished - 4 Jul 2023


  • Animals
  • Humans
  • Immune Evasion/genetics
  • Phylogeny
  • Viral Tropism
  • Lyme Disease/microbiology
  • Borrelia burgdorferi
  • Bacterial Proteins/metabolism
  • Complement Factor H/genetics
  • Complement System Proteins/genetics
  • Membrane Proteins/metabolism

Field of Science*

  • 3.3 Health sciences

Publication Type*

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database


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