Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages

Abstract

cOuter surface protein C (OspC) is one of the major lipoproteins expressed on the surface of Borrelia burgdorferi during tick feeding and the early phase of mammalian infection. OspC is required for B. burgdorferi to establish infection in both immunocompetent and SCID mice and has been proposed to facilitate evasion of innate immune defenses. However, the exact biological function of OspC remains elusive. In this study, we showed that the ospC-deficient spirochete could not establish infection in NOD-scid IL2r␥ null mice that lack B cells, T cells, NK cells, and lytic complement. The ospC mutant also could not establish infection in anti-Ly6G-treated SCID and C3H/HeN mice (depletion of neutrophils). However, depletion of mononuclear phagocytes at the skin site of inoculation in SCID and C3H/HeN mice allowed the ospC mutant to establish infection in vivo. In phagocyte-depleted mice, the ospC mutant was able to colonize the joints and triggered neutrophilia during dissemination. Furthermore, we found that phagocytosis of green fluorescent protein (GFP)-expressing ospC mutant spirochetes by murine peritoneal macrophages and human THP-1 macrophage-like cells, but not in PMN-HL60, was significantly higher than parental wild-type B. burgdorferi strains, suggesting that OspC has an antiphagocytic property. In addition, overproduction of OspC in spirochetes also decreased the uptake of spirochetes by murine peritoneal macrophages. Together, our findings provide evidence that mononuclear phagocytes play a key role in clearance of the ospC mutant and that OspC promotes spirochetes' evasion of macrophages during early Lyme borreliosis. L yme disease, the most prevalent vector-borne illness in the United States (1), is a multisystem inflammatory disorder caused by infection with the spirochete Borrelia burgdorferi (2, 3). This spirochete is maintained in nature through a complex enzootic cycle involving Ixodes ticks and various small-mammal hosts. Humans, as accidental hosts, become infected after B. burgdorferiinfected ticks feed on them (4). Spirochetes replicate in the skin, spread locally, and induce an inflammatory response with a symptom known as erythema migrans, observed in most patients (2, 4). During disseminated infection, B. burgdorferi colonizes multiple tissues, leading to different clinical manifestations, including arthritis, myocarditis, and neurological and/or cutaneous abnormalities (2, 4). This acute, disseminated stage of human Lyme disease is largely recapitulated using inbred mouse strains which are susceptible to B. burgdorferi infection and develop carditis and subacute arthritis (5). Thus, the murine model provides a powerful tool to elucidate the role of spirochete virulence factors and host immunological responses during Lyme disease pathogenesis (4).The B. burgdorferi genome encodes a large number of surface lipoproteins, many of which are expressed during mammalian infection (4, 6, 7). One of these lipoproteins is the major outer surface protein C (OspC), whose production is induced within inf...

Functional Equivalence of OspA and OspB, but Not OspC, in Tick Colonization by Borrelia burgdorferi

“…The inability of OspC to substitute for OspA indicates that the requirements for tick colonization may include a sequence-specific or structural component. Our data are consistent with previous findings (18,29,47) and support the model that (i) OspA is functional within the tick, because it is not normally made within the mammal and so is not recognized by antibodies in the incoming blood meal and may also bind to a midgut receptor (46); (ii) OspC is functional during early mammalian infection, when a few spirochetes must defend themselves against the host innate immune system in order to establish themselves in the foreign host environment (26); and (iii) VlsE functions while varying to evade host immunity during persistent infection within a mammal, when the spirochetes have disseminated to multiple tissues. Each protein has unique features that optimize it to the time and place at which it is synthesized.…”

“…OspB mutants have also been reported to be defective in tick colonization (22), but other data indicate that OspB serves a minor role in the infectious cycle, at least in a laboratory setting (18). OspC is required for early mammalian infection (23)(24)(25), and a recent study indicates that OspC blocks the phagocytosis of spirochetes by macrophages in the skin (26). VlsE is required for persistent infection, except in immunocompromised mice (16,17).…”

Host Immune Evasion by Lyme and Relapsing Fever Borreliae: Findings to Lead Future Studies for Borrelia miyamotoi

“…OspC has diverse roles, many of which are essential for transmission from Ixodes and establishing infection in mammals (209–216). These studies were key in demonstrating that ospC is upregulated during the early stages of infection, downregulated after infection has been established, and deleting or overexpressing ospC results in spirochetes that are quickly cleared from a host.…”

“…As discussed above, OspC protects Borrelia by binding Salp15. OspC also prevents phagocytosis by macrophages (216). In addition, several OspC types have been identified and correlated with a strains ability to establish infection in hosts and reservoirs (217–222).…”

Lyme disease: time for a new approach?

“…Recent evidence shedding light on how spirochaetes of the Borrelia genus evade host immune defences and survive antibiotic challenge [10][11][12][13][14][15] threaten current beliefs about the persistence of infection, one of the largest points of contention in the medical community. The possibility of persistent infection has important implications for diagnosis, treatment, and doctor-patient interactions.…”