Lipoproteome screening of the Lyme disease agent identifies novel inhibitors of antibody-mediated complement killing

Abstract

Spirochetal pathogens such as the causative agent of Lyme disease, Borrelia burgdorferi sensu lato, encode an abundance of lipoproteins; however, due in part to their evolutionary distance from more well-studied bacteria such as Proteobacteria and Firmicutes, very few spirochetal lipoproteins have assigned functions. Indeed, B. burgdorferi devotes almost 8% of its genome to lipoprotein genes and interacts with its environment primarily through the production of at least eighty surface-exposed lipoproteins throughout its tick vector-vertebrate host lifecycle (57). Several B. burgdorferi lipoproteins have been shown to serve diverse roles, such as cellular adherence or immune evasion, but the functions for most B. burgdorferi surface lipoproteins remain unknown. In this study, we developed a B. burgdorferi lipoproteome screening platform utilizing intact spirochetes that enables the identification of previously unrecognized host interactions. As spirochetal survival in the bloodstream is essential for dissemination, we targeted our screen to C1, the first component of the classical (antibody-mediated) complement pathway. We identified two high-affinity C1 interactions by the paralogous lipoproteins, ErpB and ErpQ. Using biochemical, microbiological, and biophysical approaches, we demonstrated that ErpB and ErpQ inhibit the activated forms of the C1 proteases, C1r and C1s, and represent a new mechanistic class of C1 inhibitors that protect the spirochete from antibody-mediated complement killing by allosteric regulation. In addition to identifying a novel mode of complement inhibition, our study establishes a lipoproteome screening methodology as a discovery platform for identifying direct host-pathogen interactions that are central to the pathogenesis of spirochetes, such as the Lyme disease agent.

The Consistent Tick-Vertebrate Infectious Cycle of the Lyme Disease Spirochete Enables Borrelia burgdorferi To Control Protein Expression by Monitoring Its Physiological Status

“…1 ) ( 98 , 99 ). Consistent with that expression profile, all identified functions of Erp proteins involve interactions between B. burgdorferi and its vertebrate hosts, including binding to complement factors H, C1r, and C1s, plasmin, laminin, and glycosaminoglycans ( 100 – 104 ).…”

Erp and Rev adhesins of the Lyme disease spirochete’s ubiquitous cp32 prophages assist the bacterium during vertebrate infection

“…The ErpB, ErpM and ErpQ proteins of strain B31 (confusingly called ElpB, ElpM and ElpQ in the publications) were recently demonstrated to bind complement factors C1s and C1r (87, 88). Adhesion of those host proteins onto the borrelial surface appears to afford protection from the classical arm of complement.…”