Complement inhibition by a unique cluster of immunomodulatory outer surface proteins of Borrelia recurrentis

Abstract Borrelia recurrentis, the agent of louse-borne relapsing fever, causes a poverty-associated, infectious disease of high mortality. Here, we identified and characterized five Complement targeting and Host Interacting proteins, ChiA to ChiE displaying immunomodulatory functions. Almost all Chi homologs inhibit complement activation by direct binding of key components, block membrane attack complex formation, and interact with plasminogen. Borrelia proteins protect susceptible spirochetes from complement-mediated killing and ChiB, ChiC, and ChiD facilitate serum resistance. X-ray structures of ChiA and ChiB, along with AlphaFold models of ChiC, ChiD, and ChiE, reveal a conserved, compact eight-helix fold with a central hydrophobic pocket and a unique S-domain-feature distinct from all known Borrelia proteins. Notably, ChiC and ChiE harbor conserved cysteines forming a reversible disulfide bridge, indicating redox-responsive function. Our findings identify a protein family of functionally related immune evasion factors, advancing our understanding of the underlying mechanisms of complement resistance in this neglected, human pathogenic microorganism.