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

ABSTRACT: The optimal protective immunity against Chlamydia trachomatis (C.t.) is still not fully resolved. One of the unresolved issues concerns the importance of resident immunity, since a recent study showed that optimal protection against a transcervical (TC) infection required genital tissue-resident memory T cells. An important question in the Chlamydia field is therefore if a parenteral vaccine strategy, inducing only circulating immunity primed at a nonmucosal site, should be pursued by Chlamydia vaccine developers. To address this question we studied the protective efficacy of a parenteral Chlamydia vaccine, formulated in the Th1/Th17 T cell-inducing adjuvant CAF01. We found that a parenteral vaccination induced significant protection against a TC infection and against development of chronic pathology. Protection correlated with rapid recruitment of Th1/Th17 T cells to the genital tract (GT), which efficiently prevented infection-driven generation of low quality Th1 or Th17 T cells, and instead maintained a pool of high quality multifunctional Th1/Th17 T cells in the GT throughout the infection. After clearance of the infection, a pool of these cells settled in the GT as tissue-resident Th1 and Th17 cells expressing CD69 but not CD103, CD49d, or CCR7, where they responded rapidly to a reinfection. These results show that a nonmucosal parenteral strategy inducing Th1 and Th17 T cells mediates protection against both infection with C.t. as well as development of chronic pathology, and lead to post-challenge protective tissue-resident memory immunity in the genital tract.

SUBMITTER: Nguyen NDNT

PROVIDER: S-EPMC6978417 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Maternal immunity partially protects newborn mice against a Chlamydia trachomatis intranasal challenge.

Project description:To determine the role of maternal immunity in protecting newborn mice against a Chlamydia trachomatis infection, female BALB/c mice were immunized intranasally (i.n.) with 10? inclusion forming units (IFU) of the C. trachomatis mouse pneumonitis biovar (MoPn). As a control, another group of female mice was sham-immunized i.n. with HeLa cell extracts. Immunized animals mounted strong immune responses as evidenced by high Chlamydia-specific antibody titers in serum and milk. Newborn mice born from immunized and sham-immunized dams were challenged i.n. with 10³IFU of MoPn at two post-natal days (PND). Following inoculation, newborn mice were euthanized at 7- and 18-PND and the lungs, spleen and intestine were cultured for Chlamydia. Overall, no significant differences were observed between the mice born from and fed by immunized dams and mice born from and fed by sham-immunized dams. Of the mice born from immunized dams, 75 and 25% had positive lung cultures at 7- and 18-PND, respectively. Of the mice born from sham-immunized dams, 82 and 50% had positive lung cultures for those same days. When the number of IFU recovered from the lungs and spleens was compared between the two groups no significant differences were observed. However, when the number of IFU recovered from the small intestine was compared, significant differences were observed between the two groups of newborn mice (2×10? versus 32×10? at 7-PND and 9.2×10? versus 85×10? at 18-PND). In conclusion, maternal immunity plays a limited role in protecting newborn mice against a Chlamydia infection.

| S-EPMC2949516 | biostudies-literature

Heterologous prime-boost vaccination based on Polymorphic protein D protects against intravaginal Chlamydia trachomatis infection in mice.

Project description:The control of the worldwide spread of sexually transmitted Chlamydia trachomatis (Ct) infection urgently demands the development of a preventive vaccine. In this work, we designed a vaccine based on a fragment of polymorphic protein D (FPmpD) that proved to be immunogenic enough to generate a robust systemic and mucosal IgG humoral immune response in two strains of mice. We used a heterologous prime-boost strategy, including simultaneous systemic and mucosal administration routes. The high titers of anti-PmpD antibodies elicited by this immunization scheme did not affect murine fertility. We tested the vaccine in a mouse model of Ct intravaginal infection. Anti-PmpD antibodies displayed potent neutralizing activity in vitro and protective effects in uterine tissues in vivo. Notably, the humoral immune response of PmpD-vaccinated mice was faster and stronger than the primary immune response of non-vaccinated mice when exposed to Ct. FPmpD-based vaccine effectively reduced Ct shedding into cervicovaginal fluids, bacterial burden at the genitourinary tract, and overall infectivity. Hence, the FPmpD-based vaccine might constitute an efficient tool to protect against Ct intravaginal infection and decrease the infection spreading.

| S-EPMC9030682 | biostudies-literature

Vaccination with the recombinant major outer membrane protein elicits antibodies to the constant domains and induces cross-serovar protection against intranasal challenge with Chlamydia trachomatis.

Project description:To determine the ability of the major outer membrane protein (MOMP) to elicit cross-serovar protection, groups of mice were immunized by the intramuscular (i.m.) and subcutaneous (s.c.) routes with recombinant MOMP (rMOMP) from Chlamydia trachomatis serovars D (UW-3/Cx), E (Bour), or F (IC-Cal-3) or Chlamydia muridarum strain Nigg II using CpG-1826 and Montanide ISA 720 VG as adjuvants. Negative-control groups were immunized i.m. and s.c. with Neisseria gonorrhoeae recombinant porin B (Ng-rPorB) or i.n. with Eagle's minimal essential medium (MEM-0). Following vaccination, the mice developed antibodies not only against the homologous serovar but also against heterologous serovars. The rMOMP-vaccinated animals also mounted cell-mediated immune responses as assessed by a lymphoproliferative assay. Four weeks after the last immunization, mice were challenged i.n. with 10(4) inclusion-forming units (IFU) of C. muridarum. The mice were weighed for 10 days and euthanized, and the number of IFU in their lungs was determined. At 10 days postinfection (p.i.), mice immunized with the rMOMP of C. muridarum or C. trachomatis D, E, or F had lost 4%, 6%, 8%, and 8% of their initial body weight, respectively, significantly different from the negative-control groups (Ng-rPorB, 13%; MEM-0, 19%; P < 0.05). The median number of IFU recovered from the lungs of mice immunized with C. muridarum rMOMP was 0.13 × 10(6). The median number of IFU recovered from mice immunized with rMOMP from serovars D, E, and F were 0.38 × 10(6), 7.56 × 10(6), and 11.94 × 10(6) IFU, respectively. All the rMOMP-immunized animals had significantly less IFU than the Ng-rPorB (40 × 10(6))- or MEM-0 (70 × 10(6))-immunized mice (P < 0.05). In conclusion, vaccination with rMOMP can elicit protection against homologous and heterologous Chlamydia serovars.

| S-EPMC3648024 | biostudies-literature

Formulation of the microbicide INP0341 for in vivo protection against a vaginal challenge by Chlamydia trachomatis.

Project description:The salicylidene acylhydrazide (SA) compounds have exhibited promising microbicidal properties. Previous reports have shown the SA compounds, using cell cultures, to exhibit activity against Chlamydia trachomatis, herpes simplex virus and HIV-1. In addition, using an animal model of a vaginal infection the SA compound INP0341, when dissolved in a liquid, was able to significantly protect mice from a vaginal infection with C. trachomatis. To expand upon this finding, in this report INP0341 was formulated as a vaginal gel, suitable for use in humans. Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel. In vitro formulation work generated a gel with suitable rheology and sustained drug release. A formulation containing 1 mM INP0341, 1.6 wt% Cremophor ELP (solubility enhancer) and 1.5 wt% poly(acrylic acid) (gelling and antimicrobial agent), was chosen for studies of efficacy and toxicity using a mouse model of a vaginal infection. The gel formulation was able to attenuate a vaginal challenge with C. trachomatis, serovar D. Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection. Mouse vaginal tissue treated with the formulation showed no indication of gel toxicity. The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue. Therefore, the gel formulation described here appears to be a promising vaginal microbicide to prevent a C. trachomatis infection with the potential to be expanded to other sexually transmitted diseases.

| S-EPMC4214720 | biostudies-literature

Chlamydia trachomatis: the Persistent Pathogen.

Project description:Chlamydia trachomatis is an obligate intracellular bacterium whose only natural host is humans. Although presenting as asymptomatic in most women, genital tract chlamydial infections are a leading cause of pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy. C. trachomatis has evolved successful mechanisms to avoid destruction by autophagy and the host immune system and persist within host epithelial cells. The intracellular form of this organism, the reticulate body, can enter into a persistent nonreplicative but viable state under unfavorable conditions. The infectious form of the organism, the elementary body, is again generated when the immune attack subsides. In its persistent form, C. trachomatis ceases to produce its major structural and membrane components, but synthesis of its 60-kDa heat shock protein (hsp60) is greatly upregulated and released from the cell. The immune response to hsp60, perhaps exacerbated by repeated cycles of productive infection and persistence, may promote damage to fallopian tube epithelial cells, scar formation, and tubal occlusion. The chlamydial and human hsp60 proteins are very similar, and hsp60 is one of the first proteins produced by newly formed embryos. Thus, the development of immunity to epitopes in the chlamydial hsp60 that are also present in the corresponding human hsp60 may increase susceptibility to pregnancy failure in infected women. Delineation of host factors that increase the likelihood that C. trachomatis will avoid immune destruction and survive within host epithelial cells and utilization of this knowledge to design individualized preventative and treatment protocols are needed to more effectively combat infections by this persistent pathogen.

| S-EPMC5629669 | biostudies-literature

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| PRJDB4200 | ENA

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| PRJNA175480 | ENA

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| PRJNA262506 | ENA

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