title: Versatile roles of CspA orthologs in complement inactivation of serum-resistant Lyme disease spirochetes.
abstract: CspA of the Lyme disease spirochete Borrelia burgdorferi represents a key molecule in immune evasion, protecting borrelial cells from complement-mediated killing. As previous studies focused almost exclusively on CspA of B. burgdorferi, here we investigate the different binding capacities of CspA orthologs of Borrelia burgdorferi, B. afzelii, and B. spielmanii for complement regulator factor H and plasminogen and their ability to inhibit complement activation by either binding these host-derived plasma proteins or independently by direct interaction with components involved in formation of the lethal, pore-like terminal complement complex. To further examine their function in serum resistance in vivo, a serum-sensitive B. garinii strain was used to generate spirochetes, ectopically producing functional CspA orthologs. Irrespective of their species origin, all three CspA orthologs impart resistance to complement-mediated killing when produced in a serum-sensitive B. garinii surrogate strain. To analyze the inhibitory effect on complement activation and to assess the potential to inactivate C3b by binding of factor H and plasminogen, recombinant CspA orthologs were also investigated. All three CspA orthologs simultaneously bound factor H and plasminogen but differed in regard to their capacity to inactivate C3b via bound plasmin(ogen) and inhibit formation of the terminal complement complex. CspA of B. afzelii binds plasmin(ogen) and inhibits the terminal complement complex more efficiently than CspA of B. burgdorferi and B. spielmanii. Taken together, CspA orthologs of serum-resistant Lyme disease spirochetes act as multifunctional evasion molecules that inhibit complement on two central activation levels, C3b generation and assembly of the terminal complement complex.
authors.affiliation: Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt, Frankfurt, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Hammerschmidt
authors.forename: Arno
authors.initials: A
authors.lastname: Koenigs
authors.forename: Corinna
authors.initials: C
authors.lastname: Siegel
authors.forename: Teresia
authors.initials: T
authors.lastname: Hallström
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wallich
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.forename: Peter
authors.initials: P
authors.lastname: Kraiczy
mesh_terms: D000704:Analysis of Variance; D001426:Bacterial Proteins / Q000502:physiology*; D001433:Bacteriolysis / Q000502:physiology; D001770:Blood Bactericidal Activity; D001898:Borrelia / Q000502:physiology; D025065:Borrelia burgdorferi / Q000502:physiology*; D002478:Cells, Cultured; D003179:Complement C3b / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008193:Lyme Disease / Q000276:immunology / Q000382:microbiology*; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; C062260:cold shock protein CS7.4, Bacteria; D003179:Complement C3b; D010958:Plasminogen; D003165:Complement System Proteins