Borrelia burgdorferi, an extracellular pathogen, circumvents osteopontin in inducing an inflammatory cytokine response

Abstract

A classic proinflammatory T helper cell type 1 (TH1) response directed against intracellular pathogens includes the cytokine osteopontin, which acts predominantly on macrophages, where it induces the secretion of interleukin (IL)-12 and suppresses the secretion of IL-10. As cell-mediated immune responses play an important role in the resistance to Lyme arthritis, a manifestation of infection by the extracellular pathogen Borrelia burgdorferi, we tested the hypothesis that osteopontin may be required to induce T(H)1 responses and inflammation. The role of osteopontin was tested in vivo and using ex vivo macrophages in B6129F3 mice susceptible to experimental Lyme arthritis. Mice of this genetic background and those fully backcrossed to C57BL/6, which lacked osteopontin expression (spp1-/-), were as susceptible to B. burgdorferi-induced arthritis as littermate controls. Furthermore, equal numbers of spirochetes, as measured by quantitative polymerase chain reaction of the B. burgdorferi gene recA in spp1-/- and B6129F3 wild-type littermates, suggested that susceptibility to infection was not dependent on this cytokine. Neither of the B6129F3 parental mouse strains lacked the ability to secrete osteopontin. spp1-/- mice and controls had immunoglobulin G2 titers, suggestive of a TH1 response. B. burgdorferi was able to directly stimulate the secretion of the proinflammatory cytokines IL-12 and tumor necrosis factor alpha from wild-type and spp1-/- macrophages alike. These results indicate that the usually critical role of osteopontin in the induction of cellular immune responses to intracellular pathogens was circumvented by the ability of the extracellular pathogen B. burgdorferi to induce macrophages directly to produce proinflammatory cytokines.

Osteopontin Impairs Host Defense during Established Gram-Negative Sepsis Caused by Burkholderia pseudomallei (Melioidosis)

“…In this respect, it should be noted that in a model of murine tuberculosis we also did not detect an effect of OPN on the Th1 response [29]. Similarly, normal immune responses of OPN KO mice have been reported during vaccinia virus, influenza virus, Listeria monocytogenes [46] and Borrelia burgdorferi infection [47], [48]. With regard to murine melioidosis it should be noted that natural killer cells, rather than T cells, are the main producers of IFN-γ [12].…”

Coxiella burnetii Nine Mile II proteins modulate gene expression of monocytic host cells during infection

“…Interestingly, of the thirty-six host genes that met our criteria (Table 1) for C. burnetii protein driven expression changes, four are cytokines (IL8, CCL2, CXCL1 and SPP1). These secretory molecules are noted for chemo-attraction of phagocytic and lymphocytic cells [38-40]. C. burnetii protein(s) appear to reduce the RNA levels of each of these four genes in infected THP-1 cells relative to those found in infected cells transiently inhibited with CAM.…”

Effect of Borrelia burgdorferi OspC at the Site of Inoculation in Mouse Skin

“…Macrophages are the cells that first respond to the site of Borrelia burgdorferi infection (42), and there have been extensive studies on macrophage infections with Borrelia burgdorferi in vitro (15,23,24,35,39,42,44,46,53). The hypothesis that OspC might play a role in the interaction of the bacteria with the innate immune response led to the investigation of the interaction of macrophages with WT and ospC mutant bacteria.…”

“…These cytokines were chosen because they are known to be secreted during infections of macrophages with Borrelia burgdorferi and have proinflammatory (TNF-␣, KC, and MCP-1) and anti-inflammatory (IL-10) actions (4,8,15,24,27,35,46,53). To determine whether any observed differences in RNA transcript levels correspond to differences in cytokine production, the supernatants from each well were also analyzed for cytokine content.…”

“…Primary cultures of bone marrow-derived macrophages (BMMs) were prepared and used for the in vitro infections of macrophages with B. burgdorferi essentially as previously described (15,58). The marrow of four femurs (two mice) per mouse strain was pooled for each experiment.…”