Borrelia burgdorferi ErpB and ErpQ inhibit C1 complex of the classical pathway of complement through a novel mechanism

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Ryan Garrigues (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: The complement system is an organized proteolytic cascade of dozens of proteins that functions in the recognition, opsonization, and lysis of pathogenic and altered-host cells. Bloodborne pathogens like the etiologic agent of Lyme disease, Borrelia burgdorferi, encounter complement during their bloodmeal and in their dissemination through the body. Therefore, to avoid complement mediated destruction, these pathogens have developed mechanisms that aid in complement evasion and defense. The spirochete B. burgdorferi, has nearly a dozen known complement recruiting or inhibiting surface exposed lipoproteins. Here, we uncover a novel inhibitory mechanism for two surface exposed lipoproteins, ErpB and ErpQ, that were recently identified using a lipoprotein gain of function library. Using surface plasmon resonance, ErpB and ErpQ were found to bind C1 complex proteases C1r and C1s with high affinity. Gel-based biochemical assays showed that ErpB and ErpQ specifically inhibit C1s-mediated cleavage of both C2 and C4 making them the only known bacterial inhibitors of C1s. Furthermore, they were shown to block C1s outside of the active site indicating that they function by a novel mechanism. Additional site-directed mutagenesis of C1s exosites revealed determinants for high affinity inhibitor interactions that have been shown to be important for C1s recognition of C4 outside of the active site. The discovery of a novel mechanism of complement inhibition by a medically-relevant human pathogen expands our knowledge of host pathogens interactions and contributes to previously unknown pathophysiological immune evasion by B. burgdorferi. Mechanistic studies on ErpB and ErpQ also support further understanding of molecular interactions between complement proteases and their substrates, which provides alternative means for the development of specific complement therapeutics toward complement-mediated diseases.

Additional Information

Publication

Thesis

Language: English

Date: 2023

Subjects

Complement;Protease inhibitors;Immune evasion

Email this document to