Abstract
Research on syphilis, a sexually transmitted infection caused by the non-cultivatable spirochete Treponema pallidum, has been hampered by the lack of an inbred animal model. We hypothesized that Toll-like receptor (TLR)-dependent responses are essential for clearance of T. pallidum and, consequently, compared infection in wild-type (WT) mice and animals lacking MyD88, the adaptor molecule required for signaling by most TLRs. MyD88-deficient mice had significantly higher pathogen burdens and more extensive inflammation than control animals. Whereas tissue infiltrates in WT mice consisted of mixed mononuclear and plasma cells, infiltrates in MyD88-deficient animals were predominantly neutrophilic. Although both WT and MyD88-deficient mice produced antibodies that promoted uptake of treponemes by WT macrophages, MyD88-deficient macrophages were deficient in opsonophagocytosis of treponemes. Our results demonstrate that TLR-mediated responses are major contributors to the resistance of mice to syphilitic disease and that MyD88 signaling and FcR-mediated opsonophagocytosis are linked to the macrophage-mediated clearance of treponemes.
Highlights
Syphilis is a multistage, sexually transmitted illness caused by the obligate human pathogen Treponema pallidum subsp. pallidum and characterized by protean clinical manifestations [1,2,3]
T. pallidum is thought to be cleared by macrophages via antibodymediated opsonophagocytosis [5,6,7,8,9]
Our results demonstrate that MyD88-dependent Toll-like receptor (TLR)-mediated responses contribute to the intrinsic resistance of mice to syphilitic disease
Summary
Sexually transmitted illness caused by the obligate human pathogen Treponema pallidum subsp. pallidum and characterized by protean clinical manifestations [1,2,3]. Usually in the genital region, spirochetes replicate locally, inducing an inflammatory response that results in the distinctive, painless chancre of primary syphilis. The chancre heals, indicating the local clearance of T. pallidum, by which time spirochetes have disseminated to various tissues and organs [1,2,3]. Secondary syphilis, resulting from the hematogenous dissemination of organisms, typically occurs six to eight weeks after infection. This stage of the disease most commonly involves the skin, mucous membranes and lymph nodes but can affect virtually any organ including the central nervous system [3,4,5]. Approximately one-third of patients with latent infection develop one of the recrudescent forms of disease, collectively known as tertiary syphilis [2,3,6]
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