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Garcia, BL, Zhi, H, Wager, B, Höök, M and Skare, JT (2016) Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex. PLoS Pathog. 12:e1005404


Pathogens that traffic in blood, lymphatics, or interstitial fluids must adopt strategies to evade innate immune defenses, notably the complement system. Through recruitment of host regulators of complement to their surface, many pathogens are able to escape complement-mediated attack. The Lyme disease spirochete, Borrelia burgdorferi, produces a number of surface proteins that bind to factor H related molecules, which function as the dominant negative regulator of the alternative pathway of complement. Relatively less is known about how B. burgdorferi evades the classical pathway of complement despite the observation that some sensu lato strains are sensitive to classical pathway activation. Here we report that the borrelial lipoprotein BBK32 potently and specifically inhibits the classical pathway by binding with high affinity to the initiating C1 complex of complement. In addition, B. burgdorferi cells that produce BBK32 on their surface bind to both C1 and C1r and a serum sensitive derivative of B. burgdorferi is protected from killing via the classical pathway in a BBK32-dependent manner. Subsequent biochemical and biophysical approaches localized the anti-complement activity of BBK32 to its globular C-terminal domain. Mechanistic studies reveal that BBK32 acts by entrapping C1 in its zymogen form by binding and inhibiting the C1 subcomponent, C1r, which serves as the initiating serine protease of the classical pathway. To our knowledge this is the first report of a spirochetal protein acting as a direct inhibitor of the classical pathway and is the only example of a biomolecule capable of specifically and noncovalently inhibiting C1/C1r. By identifying a unique mode of complement evasion this study greatly enhances our understanding of how pathogens subvert and potentially manipulate host innate immune systems.


PubMed PMC4725857 Online version:10.1371/journal.ppat.1005404


Bacterial Proteins/immunology; Borrelia burgdorferi/immunology; Complement Activation/immunology; Complement C1/immunology; Complement Pathway, Classical/immunology; Enzyme-Linked Immunosorbent Assay; Host-Parasite Interactions/immunology; Humans; Immune Evasion/immunology; Immunoblotting; Immunoprecipitation; Lyme Disease/immunology



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status


GO:0004867: complement binding



C1r binding protein. Figure 5A-E shows C1r binding to BBK32 Full-length and the C-terminal of BBK32 through surface plasmon resonance assays. Far Western blot analysis was used to confirm this interaction. Waiting on new GO term - Complement component C1r binding. Borrelia burgdorferi

CACAO 13526


GO:0045959: negative regulation of complement activation, classical pathway



Fig. 7A-D BBK32 from Borrelia burgdorferi is shown to inhibit autocatalysis of C1r and subsequent C1r cleavage of C1s within the C1 complex.



GO:0048519: negative regulation of biological process



Figure 4A-C shows use of classical pathway (CP)-mediated hemolysis assays using absorbance to measure cell lysis. Performed with BBK32 N-terminal, C-termainl, and full-length protein Waiting on new GO term Borrelia burgdorferi



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