CspA from Borrelia burgdorferi inhibits the terminal complement pathway

In order to survive and persist in an immunocompetent human host, Borrelia burgdorferi controls the human immune attack and blocks the damaging effects of the activated complement system. These Gram-negative spirochetes use CspA (CRASP-1) and four additional immune evasion proteins to bind combinations of human plasma regulators, including factor H, factor H-like protein 1 (FHL-1), complement factor H-related protein 1 (CFHR1), CFHR2, CFHR5, and plasminogen. As many microbial immune evasion proteins have multiple functions, we hypothesized that CspA has additional roles in complement or immune control. Here, we identify CspA as a terminal complement inhibitor. Borrelial CspA binds the human terminal complement components C7 and C9 and blocks assembly and membrane insertion of the terminal complement complex (TCC). CspA inhibits TCC assembly at the level of C7, as revealed by hemolytic assays, and inhibits polymerization of C9. CspA, when ectopically expressed on the surface of serum-sensitive Borrelia garinii, blocks TCC assembly on the level of C7 and induces serum resistance in the transformed bacteria. This CspA-mediated serum resistance and terminal complement pathway inhibition allow B. burgdorferi to survive in the hostile environment of human plasma.

The present study defines a new mechanism by which the pathogenic bacterium Borrelia burgdorferi controls the terminal complement pathway of the human host to survive in human serum. The borrelial CspA binds to terminal pathway proteins C7 and C9 and inhibits the terminal complement pathway at the step of C7 and thereby inhibits terminal complement complex (TCC) assembly and membrane insertion. CspA blocks TCC assembly and insertion when expressed at the bacterial surface. CspA is the first TCC inhibitor cloned and functionally characterized from a Gram-negative bacterium. This identification of a bacterial TCC inhibitor of pathogen origin expands our knowledge of complement evasion of pathogenic bacteria and shows that pathogenic bacteria target the terminal pathway of complement. Thus, CspA as a central microbial virulence factor can represent an interesting biomarker and a target to develop new therapeutics and vaccines against borreliae.