BGA66 and BGA71 facilitate complement resistance of Borrelia bavariensis by inhibiting assembly of the membrane attack complex

• Published in: Molecular microbiology Vol. 99; no. 2; pp. 407 - 424
• Main Authors: Hammerschmidt, Claudia, Klevenhaus, Yvonne, Koenigs, Arno, Hallström, Teresia, Fingerle, Volker, Skerka, Christine, Pos, Klaas Martinus, Zipfel, Peter F., Wallich, Reinhard, Kraiczy, Peter
• Format: Journal Article
• Language: English
• Published: England 01.01.2016
• Subjects: Animals; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Borrelia; Borrelia burgdorferi - genetics; Borrelia burgdorferi - immunology; Complement Membrane Attack Complex - genetics; Complement Membrane Attack Complex - immunology; Complement System Proteins - immunology; Humans; Lyme Disease - immunology; Lyme Disease - microbiology; Mice
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/mmi.13239

Summary Borrelia (B.) bavariensis exhibits a marked tropism for nervous tissues and frequently causes neurological manifestations in humans. The molecular mechanism by which B. bavariensis overcomes innate immunity, in particular, complement remains elusive. In contrast to other serum‐resistant spirochetes, none of the B. bavariensis isolates investigated bound complement regulators of the alternative (AP) and classical pathway (CP) or proteolytically inactivated complement components. Focusing on outer surface proteins BGA66 and BGA71, we demonstrated that both molecules either inhibit AP, CP and terminal pathway (TP) activation, or block activation of the CP and TP respectively. Both molecules bind complement components C7, C8 and C9, and thereby prevent assembly of the terminal complement complex. This inhibitory activity was confirmed by the introduction of the BGA66 and BGA71 encoding genes into a serum‐sensitive B. garinii strain. Transformed spirochetes producing either BGA66 or BGA71 overcome complement‐mediated killing, thus indicating that both proteins independently facilitate serum resistance of B. bavariensis. The generation of C‐terminally truncated proteins as well as a chimeric BGA71 protein lead to the localization of the complement‐interacting binding site within the N‐terminus. Collectively, our data reveal a novel immune evasion strategy of B. bavariensis that is directed against the activation of the TP. Upon entering the human host, Borrelia bavariensis faces the complement system as the first line of defence. To overcome complement attack, bacterial cells produce BGA66 and BGA71, two potent inhibitors of the terminal pathway, which contribute to immune evasion. These lipoproteins directly interact with complement components C7, C8 as well as C9 and thereby terminate the assembly of the pore‐forming membrane attack complex, rendering spirochetal cells highly resistant to complement‐mediated lysis.