Intravaginal Chlamydia trachomatis Challenge Infection Elicits TH1 and TH17 Immune Responses in Mice That Promote Pathogen Clearance and Genital Tract Damage

Abstract

While ascension of Chlamydia trachomatis into the upper genital tract of women can cause pelvic inflammatory disease and Fallopian tube damage, most infections elicit no symptoms or overt upper genital tract pathology. Consistent with this asymptomatic clinical presentation, genital C. trachomatis infection of women generates robust TH2 immunity. As an animal model that modeled this response would be invaluable for delineating bacterial pathogenesis and human host defenses, herein we explored if pathogen-specific TH2 immunity is similarly elicited by intravaginal (ivag) infection of mice with oculogenital C. trachomatis serovars. Analogous to clinical infection, ascension of primary C. trachomatis infection into the mouse upper genital tract produced no obvious tissue damage. Clearance of ivag challenge infection was mediated by interferon (IFN)-γ-producing CD4+ T cells, while IFN-γ signaling blockade concomitant with a single ivag challenge promoted tissue damage by enhancing Chlamydia-specific TH17 immunity. Likewise, IFN-γ and IL-17 signaling blockade or CD4+ T cell depletion eliminated the genital pathology produced in untreated controls by multiple ivag challenge infections. Conversely, we were unable to detect formation of pathogen-specific TH2 immunity in C. trachomatis-infected mice. Together, our work revealed C. trachomatis infection of mice generates TH1 and TH17 immune responses that promote pathogen clearance and immunopathological tissue damage. Absence of Chlamydia-specific TH2 immunity in these mice newly highlights the need to identify experimental models of C. trachomatis genital infection that more closely recapitulate the human host response.

Parenteral vaccination protects against transcervical infection with Chlamydia trachomatis and generate tissue-resident T cells post-challenge

“…Circulating immunity induced by a nonmucosal parenteral vaccine protect against chronic pathology in the genital tract As the presence of Th17 T cells has been suggested to correlate with increased pathology in the upper genital tract in some studies, [12][13][14][15][16] but not in others, [17][18][19] it was important to also examine the effect of the recruited T cells on development of pathology. Mice were vaccinated as described above, and at day 50 post a TC infection with 10 3 IFUs, the genital tract was analyzed for chronic pathological changes.…”

“…This is interesting since previous data suggested that Th17 T cells may have a role in inducing pathology. [12][13][14][15][16][17][18][19][20] As the Th17 T cell cytokine profile differed markedly from the Th17 cytokine profile in nonvaccinated/infected animals (that developed pathology), it could be speculated that only certain Th17 T cell subsets are associated with pathology, and that a Th17-inducing vaccine can prevent induction of the pathology-inducing Th17 T cells that are normally induced by the infection itself.…”

“…12 However, further studies of Th17 T cells are required to determine their role, in particular as previous studies suggested that this particular subset of T cells may induce pathology rather than protect against it. [12][13][14][15][16][17][18][19][20] Although a parenteral vaccine has proven effective against a vaginal infection with C.t. [21][22][23] or C.m., [24][25][26][27][28][29][30] in the TC C.t.…”

Exogenous oestrogen inhibits genital transmission of cell‐associated HIV‐1 in DMPA‐treated humanized mice

“…hPBMCs were inoculated with 600 TCID 50 of HIV‐1 BaL for 24 hour, and re‐suspended in PBS (10 8 cells/ml) for in vivo infections (portions of the HIV‐1‐infected hPBMC culture were used in a luciferase gene reporter assay to confirm HIV‐1 infectivity). For infection, hPBMC‐NSG mice were anaesthetized with xylazine and ketamine hydrochloride , and ivag inoculated with 10 6 (10 μl) of HIV‐1‐infected huPBMCs. Mice were euthanized 10 days later to assess HIV‐1 infection status.…”

IL-17 Production by γδ+ T Cells Is Critical for Inducing Th17 Responses in the Female Genital Tract and Regulated by Estradiol and Microbiota

“…Within the female genital tract (FGT), a mucosal site exposed to diverse pathogens, IL-17 has been shown to play an important role during bacterial and fungal infections, including Neisseria gonorrheae, Candida albicans, and Chlamydia trachomatis (14)(15)(16)(17)(18)(19). However, the role of IL-17 during genital viral infections has not been fully elucidated.…”