Borrelia burgdorferiouter surface protein C (OspC) binds complement component C4b and confers bloodstream survival

Abstract

Borrelia burgdorferi (Bb) is the causative agent of Lyme disease in the US, a disease that can result in carditis, and chronic and debilitating arthritis and/or neurologic symptoms if left untreated. Bb survives in the midgut of the Ixodes scapularis tick, or within tissues of immunocompetent hosts. In the early stages of infection, the bacteria are present in the bloodstream where they must resist clearance by the innate immune system of the host. We have found a novel role for OspC from B. burgdorferi and B. garinii in interactions with the complement component C4b and bloodstream survival in vivo. Our data show that OspC inhibits the classical and lectin complement pathways and competes with complement protein C2 for C4b binding. Resistance to complement is important for maintenance of the lifecycle of Bb, enabling survival of the pathogen within the host as well as in the midgut of a feeding tick when ospC expression is induced.

Blood treatment of Lyme borreliae demonstrates the mechanism of CspZ ‐mediated complement evasion to promote systemic infection in vertebrate hosts

“…The infection of WT strain B31‐A3 or strain B31‐A3Δ cspZ ‐V resulted in indistinguishable levels of bacteraemia at 7 days post infection (dpi) and tissue colonization at both 7 and 14 dpi (Figure S8A, left panel and S8B to E). Note that we were unable to detect spirochetes in the blood at 14 dpi (Figure S8A, right panel), in agreement with kinetics of bacteraemia present only at extremely early stages of murine infection (Caine et al, ).…”

“…This protein also promotes spirochete survival in the mouse bloodstream and dissemination (Caine & Coburn, ; Hyde et al, ; Seshu et al, ). Similarly, B. burgdorferi produces OspC that inactivates both classical and lectin pathways and contributes to early stages of bacteraemia (Caine et al, ; Caine & Coburn, ). In this study, we treated a cspZ ‐deficient B. burgdorferi with blood to demonstrate this CspZ's ability, by evading complement, to promote bacteraemia and/or tissue colonization (Figures and ).…”

“…Another mechanism is to express complement regulator‐binding proteins, which recruit host complement regulators to the cell surface to degrade active complement complexes (Blom et al, ; Meri, ). For example, Lyme borreliae produce OspC and BBK32, which, respectively, bind C4b and C1q to inhibit complement (Caine et al, ; Garcia, Zhi, Wager, Hook, & Skare, ). This pathogen also produces at least five distinct complement regulator‐acquiring surface proteins (CRASPs): CspA (CRASP‐1), CspZ (CRASP‐2), ErpP (CRASP‐3), ErpC (CRASP‐4), and ErpA (CRASP‐5; Kraiczy & Stevenson, ).…”

“…Incubating B. burgdorferi with mammalian blood simulates the conditions in hosts that leads to upregulation of genes that are normally expressed when spirochetes are in vertebrate hosts (Tokarz et al, ). In fact, blood treatment of spirochetes has been used to delineate the roles of several spirochete genes in vivo (Caine & Coburn, ; Caine et al, ; Y. P. Lin et al, ; Moriarty et al, ; Norman et al, ). Therefore, we hypothesized that blood treatment of spirochetes would enhance the production of CspZ thereby permitting examination of this protein in facilitating serum survival and infectivity in diverse hosts.…”

Outer surface protein polymorphisms linked to host‐spirochete association in Lyme borreliae

“…Additional Lyme borreliae proteins including BBK32 and OspC have been recently identified to promote host complement inactivation and/or facilitate the spirochete bloodstream survival and dissemination (Caine and Coburn, ; Garcia et al , ; Caine et al , ). BBK32, for example, binds to C1r to inhibit the initiation of the classical pathway, but high sequence identity of the variants among Lyme borreliae (greater than 70%) suggests that this protein is less likely to confer allelic variable and/or host‐specific complement inactivation (Probert et al , ; Garcia et al , ).…”