CD4⁺Lymphocytes and Gamma Interferon Predominate in Local Immune Responses in Early Experimental Syphilis

Abstract

The clearance of Treponema pallidum subsp. pallidum from early syphilis lesions involves infiltration of a large number of mononuclear cells and is characteristic of a cell-mediated immune response. In the present study, we sought to determine the relative abundance of different T-lymphocyte populations and Th1/Th2-associated cytokines present in testicular lesions following experimental infection with the Chicago strain of T. pallidum. Using flow cytometry, we examined the proportion of CD4 ؉ and CD8 ؉ T cells present throughout the progression and resolution of primary syphilis in the rabbit model. We related these findings to the results of real-time reverse transcription-PCR quantification of treponemal and cytokine mRNA levels. Treponemal mRNA levels reached peak values on day 18 postinfection, coincident with an initial peak in the level of T cells, which were primarily CD4 ؉ T cells. T-cell levels increased again during resolution of orchitis, and there was an increased proportion of CD8 ؉ T cells. The maximum gamma interferon (IFN-␥) and interleukin-10 (IL-10) mRNA levels were observed on days 11 and 18, respectively, while only negligible amounts of IL-4 and IL-2 were detected throughout the infection. In addition to showing the temporal relationship between treponemal burden and T-cell responses during lesion progression, our results also demonstrate that the composition of the T-cell population changes during lesion resolution. The presence of the mRNA for IFN-␥, but not IL-4, is consistent with cytokine expression in human syphilis and provides further support for the hypothesis that there is a Th1 predominance during the early immune response to T. pallidum.Natural infection with Treponema pallidum subsp. pallidum, the causative agent of syphilis, results in the formation of a primary lesion, or chancre, at the site of infection. A vigorous immune response develops early during infection and results in local clearance of the majority of treponemes and resolution of the primary lesions. The cell phenotypes and cytokines present in early syphilitic lesions during human infection and experimental infection in the rabbit models suggest that the early immune response to T. pallidum is characteristic of a delayedtype hypersensitivity or Th1 response. A large number of mononuclear cells, consisting mostly of T cells and macrophages, infiltrate early lesions prior to bacterial clearance and lesion healing (15,23,24,28). CD4 ϩ helper T cells are believed to mediate bacterial clearance primarily through the production of cytokines, such as gamma interferon (IFN-␥), which activate macrophages (14, 30). Macrophages then engulf and kill opsonized treponemes (2, 17). There is also evidence that activated cytolytic (CD8 ϩ ) T lymphocytes participate in the local immune response within lesions, although their role in clearance remains unclear (18, 31). An important role for antibody in bacterial clearance has also been demonstrated (3, 4, 16); however, reports vary on the relative abundance of B cells within the le...

Host Defense Mechanisms in Secondary Syphilitic Lesions

“…11,6 In functional studies phagocytosis of opsonized T. pallidum by macrophages, 9,10 activated by IFN-␥, 10 has been demonstrated, and degraded T. pallidum organisms were found in phagocytic vacuoles of macrophages. 23,5 These observations combined with the fact that treponemas are extracellular bacteria gave reason to speculate that macrophages, activated by IFN-␥-pro- ϩ T-cells were the most likely candidates in rabbit models of syphilis infection, 19 other studies indicated a possible role for CD8 ϩ T-cells in providing this macrophage-activating cytokine. 7 The cellular course of events described in animals and also observed in humans infected with T. pallidum is similar to what we observed in our HIV Ϫ syphilitic patients.…”

“…Lesional macrophages appear a few days later, which is paralleled by a sharp decline of lesional spirochetes. 4,19,20 Similarly, T-cells and macrophages are found in human primary chancres 21,22 and secondary lesions. 11,6 In functional studies phagocytosis of opsonized T. pallidum by macrophages, 9,10 activated by IFN-␥, 10 has been demonstrated, and degraded T. pallidum organisms were found in phagocytic vacuoles of macrophages.…”

Syphilis: using modern approaches to understand an old disease

“…pallidum replicates at the site of initial inoculation, dividing once every 30-33 hours (14,15), inducing a local inflammatory response that results in a painless chancre approximately 3-6 weeks after initial infection. In each chancre, proliferating spirochetes are surrounded by immune cells, including CD4 + and CD8 + T cells, plasma cells, and macrophages, which produce IL-2 and IFN-γ cytokines, indicating a Th1-skewed response (16)(17)(18)(19)(20)(21). Tissue necrosis and ulceration occur due to small vessel vasculitis, and trafficking immune cells cause a non-tender regional lymphadenopathy.…”

TpF1 fromTreponema pallidumActivates Inflammasome and Promotes the Development of Regulatory T Cells

“…During early infection, T. pallidum is able to elicit a vigorous inflammation and the ensuing adaptive immune response. The latter is a typical cell-mediated immune response, characterized by Th1 predominance, which results in the local clearance of the majority of treponemes and resolution of the primary lesions (4,5). Nevertheless, although cell-mediated immune responses take part in the course of syphilis, T. pallidum often manages to evade eradication and, in untreated individuals, may trigger chronic infection.…”