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The obligate intracellular bacterium Chlamydia trachomatis is the most common cause of bacterial sexually transmitted disease in the United States and the leading cause of preventable blindness worldwide. Prior exposure to C. trachomatis has been shown to provide incomplete protection against subsequent infection. One possible explanation for the limited immunity afforded by prior C. trachomatis infection is poor activation of Chlamydia-specific memory CD8+ T cells. In this study, we examined the development of CD8+ memory T cell responses specific for the Chlamydia Ag CrpA. The percentage of CrpA63-71-specific T cells expressing an effector memory T cell phenotype (IL-7R+ CD62low) was dramatically diminished in mice immunized with C. trachomatis, compared with mice immunized with vaccinia virus expressing the CrpA protein. These alterations in memory T cell development were correlated with a significant reduction in the capacity of convalescent mice to mount an enhanced recall response to Chlamydia Ags, compared with the primary response. CrpA-specific memory T cells primed during VacCrpA infection also failed to respond to a challenge with Chlamydia. We therefore investigated whether C. trachomatis infection might have a global inhibitory effect on CD8+ T cell activation by coinfecting mice with C. trachomatis and Listeria monocytogenes and we found that the activation of Listeria-specific naive and memory CD8+ T cells was reduced in the presence of C. trachomatis. Together, these results suggest that Chlamydia is able to alter the development of CD8+ T cell responses during both primary and secondary infection, perhaps accounting for the incomplete protection provided by prior Chlamydia infection. 相似文献
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Jayarapu K Kerr M Ofner S Johnson RM 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(11):6911-6920
Chlamydia trachomatis serovars D-K are sexually transmitted intracellular bacterial pathogens that replicate in epithelial cells lining the human reproductive tract. It is clear from knockout mice and T cell depletion studies using Chlamydia muridarum that MHC class II and CD4 T cells are critical for clearing bacteria from the murine genital tract. It is not clear how CD4 T cells interact with infected epithelial cells to mediate bacterial clearance in vivo. Previous work using an epithelial tumor cell line showed that a Chlamydia-specific CD4 T cell clone was able to inhibit C. muridarum replication in vitro via induction of epithelial NO production. We have previously shown that Chlamydia-specific CD4 T cell clones can recognize and be activated by infected reproductive tract epithelial cells and block Chlamydia replication in them. We extend those observations by investigating the mechanism used by a panel of CD4 T cell clones to control Chlamydia replication in epithelial cells. We found that Chlamydia-specific CD4 T cell clones were cytolytic, but that cytolysis was not likely critical for controlling C. muridarum replication. For one, CD4 T cell clone-induced epithelial NO production was critical for controlling replication; however, the most potent CD4 T cell clones were dependent on T cell degranulation for replication control with only a minor additional contribution from NO production. We discuss our data as they relate to existing knockout mouse studies addressing mechanisms of T cell-mediated control of Chlamydia replication and their implications for intracellular epithelial pathogens in mouse models. 相似文献
4.
DC Gondek AJ Olive G Stary MN Starnbach 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(5):2441-2449
Chlamydia trachomatis infection is the most common bacterial sexually transmitted disease in the United States. Chlamydia infections that ascend to the upper genital tract can persist, trigger inflammation, and result in serious sequelae such as infertility. However, mouse models in which the vaginal vault is inoculated with C. trachomatis do not recapitulate the course of human disease. These intravaginal infections of the mouse do not ascend efficiently to the upper genital tract, do not cause persistent infection, do not induce significant inflammation, and do not induce significant CD4(+) T cell infiltration. In this article, we describe a noninvasive transcervical infection model in which we bypass the cervix and directly inoculate C. trachomatis into the uterus. We show that direct C. trachomatis infection of the murine upper genital tract stimulates a robust Chlamydia-specific CD4(+) T cell response that is both necessary and sufficient to clear infection and provide protection against reinfection. 相似文献
5.
Rhea N. Coler Ajay Bhatia Jean-Francois Maisonneuve Peter Probst Brenda Barth Pamela Ovendale Hang Fang Mark Alderson Yves Lobet Joe Cohen Pascal Mettens & Steven G. Reed 《FEMS immunology and medical microbiology》2009,55(2):258-270
Chlamydia trachomatis infection is the most common sexually transmitted bacterial infection worldwide, with over 91 million cases estimated annually. An effective subunit vaccine against Chlamydia may require a multivalent subunit cocktail of antigens in a single formulation for broad coverage of a heterogeneous major histocompatibility complex population. Herein, we describe the identification of novel C. trachomatis antigens by CD4+ and CD8+ T-cell expression cloning, serological expression cloning, and an in silico analysis of the C. trachomatis genome. These antigens elicited human CD4+ T-cell responses, and a subset proved to be immunogenic and protective when administered as immunoprophylactic vaccines against C. trachomatis challenge. Candidate vaccines consisting of the prioritized C. trachomatis antigens adjuvanted in a GlaxoSmithKline proprietary AS01B adjuvant were prioritized based on induction of solid protection against challenge in C57BL/6 and BALB/c mice with C. trachomatis . Some of the vaccines prevented bacterial shedding and colonization of the upper genital tract to varying degrees by mechanisms that may include CD4+ T cells. 相似文献
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《Microbes and infection / Institut Pasteur》2017,19(11):536-545
Chlamydia muridarum induction of mouse hydrosalpinx, depending on both tubal infection and inflammation, has been used for investigating Chlamydia trachomatis pathogenesis. We now report that IL-6 both inhibits C. muridarum infection and exacerbates pathogenicity in the mouse genital tract. When intravaginally inoculated with a high dose of C. muridarum, IL-6-deficient mice developed more extensive genital tract infection with severe hydrosalpinx, suggesting that IL-6 is required for controlling the high dose infection but not essential for C. muridarum-induced pathology. However, at a low dose, IL-6-deficient mice still developed more extensive infection in the genital tract but no longer with significant pathology, suggesting that IL-6 is required for both controlling the low dose infection and exacerbating the low dose infection-induced pathology. The lack of hydrosalpinx in IL-6-deficient mice correlated with significantly reduced inflammatory infiltration in the oviduct tissue and decreased spleen CD4+ and CD8+ T cells that produce TNFα. Thus, IL-6-dependent pathways are important for both limiting chlamydial colonization in the genital tract mucosal tissues regardless of the infection doses and exacerbating chlamydial pathogenicity in the upper genital tract when IL-6-independent pathogenic mechanisms are not yet activated with a low infection dose. 相似文献
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Immunoproteomic discovery of novel T cell antigens from the obligate intracellular pathogen Chlamydia 总被引:3,自引:0,他引:3
Karunakaran KP Rey-Ladino J Stoynov N Berg K Shen C Jiang X Gabel BR Yu H Foster LJ Brunham RC 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(4):2459-2465
Chlamydia infections cause substantial morbidity worldwide and effective prevention will depend on a vaccine. Since Chlamydia immunity is T cell-mediated, a major impediment to developing a molecular vaccine has been the difficulty in identifying relevant T cell Ags. In this study, we used a combination of affinity chromatography and tandem mass spectrometry to identify 13 Chlamydia peptides among 331 self-peptides presented by MHC class II (I-A(b)) molecules from bone marrow-derived murine dendritic cells infected with Chlamydia muridarum. These MHC class II-bound peptides were recognized by Chlamydia-specific CD4 T cells harvested from immune mice and adoptive transfer of dendritic cells pulsed ex vivo with the peptides partially protected mice against intranasal and genital tract Chlamydia infection. The results provide evidence for lead vaccine candidates for a T cell-based subunit molecular vaccine against Chlamydia infection suitable for human study. 相似文献
8.
Acquired immunity to murine Chlamydia trachomatis genital tract reinfection has long been assumed to be solely dependent on cell-mediated immunity. However, in this study, we identify a previously unrecognized protective role for Ab. Immunity develops in Ab-deficient mice following the resolution of primary chlamydial genital infection. Subsequent depletion of CD4+ T cells, but not CD8+ T cells, in those immune Ab-deficient mice before secondary infectious challenge, resulted in an infection that did not resolve. Passive immunization with immune (convalescent) serum conferred a marked level of protective immunity to reinfection, which was characterized by a striking decrease in bacterial shedding, from >100,000 inclusion forming units to fewer than 10 inclusion forming units, and a shortened duration of infection. Furthermore, mAbs to the chlamydial major outer membrane protein and LPS conferred significant levels of immunity to reinfection and reduced chlamydial shedding by >100-fold. Anti-heat shock protein 60 mAb had no protective effect. In contrast to the marked protective efficacy of immune serum on reinfection, the course of primary infection was essentially unaltered by the passive transfer of immune serum. Our results convincingly demonstrate that Abs contribute importantly to immunity to chlamydial genital tract reinfection, and that Ab-mediated protection is highly dependent on CD4+ T cell-mediated adaptive changes that occur in the local genital tract tissues during primary infection. These results impact our understanding of immunity to chlamydial genital infection and may provide important insight into vaccine development. 相似文献
9.
Control of infection by Chlamydia trachomatis usually requires the production of interferon-gamma. Whilst this can be produced by CD4+ and CD8+ T lymphocytes, natural killer (NK) cells are another important source of this cytokine, and are known to be recruited early to the infected genital tract. We show that both IL-12 and IL-18, which synergise to stimulate NK cells to produce interferon-gamma, are produced following the infection of dendritic cells and epithelial cells respectively, since supernatants from infected cells could substitute for recombinant cytokines. These results suggest that conditions, which lead to NK cell production of interferon-gamma will be present at the site of infection, where epithelial cells are the primary targets of infection and dendritic cells within the epithelium can also access the bacterium. 相似文献
10.
The obligate intracellular pathogen Chlamydia trachomatis is the most common cause of bacterial sexually transmitted diseases in the United States. In women C. trachomatis can establish persistent genital infections that lead to pelvic inflammatory disease and sterility. In contrast to natural infections in humans, experimentally induced infections with C. trachomatis in mice are rapidly cleared. The cytokine interferon-γ (IFNγ) plays a critical role in the clearance of C. trachomatis infections in mice. Because IFNγ induces an antimicrobial defense system in mice but not in humans that is composed of a large family of Immunity Related GTPases (IRGs), we questioned whether mice deficient in IRG immunity would develop persistent infections with C. trachomatis as observed in human patients. We found that IRG-deficient Irgm1/m3((-/-)) mice transiently develop high bacterial burden post intrauterine infection, but subsequently clear the infection more efficiently than wildtype mice. We show that the delayed but highly effective clearance of intrauterine C. trachomatis infections in Irgm1/m3((-/-)) mice is dependent on an exacerbated CD4(+) T cell response. These findings indicate that the absence of the predominant murine innate effector mechanism restricting C. trachomatis growth inside epithelial cells results in a compensatory adaptive immune response, which is at least in part driven by CD4(+) T cells and prevents the establishment of a persistent infection in mice. 相似文献
11.
Plasmid-deficient Chlamydia muridarum fail to induce immune pathology and protect against oviduct disease 总被引:3,自引:0,他引:3
O'Connell CM Ingalls RR Andrews CW Scurlock AM Darville T 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(6):4027-4034
Chlamydia trachomatis is the most prevalent sexually transmitted bacterial infection in the world. In women, genital infection can cause endometritis and pelvic inflammatory disease with the severe sequelae of ectopic pregnancy or infertility. Chlamydia sp. do not damage tissues directly, but induce an injurious host inflammatory response at the infected site. In the murine model of genital disease with Chlamydia muridarum, TLR2 plays a role in both early production of inflammatory mediators and development of chronic oviduct pathology. We report the results of studies with plasmid-cured C. muridarum mutants that retain the ability to infect the murine genital tract, but fail to cause disease in the oviduct. These mutants do not stimulate TLR2-dependent cytokine production in mice, nor in innate immune cells or epithelial cells in vitro. They induce an effective Th1 immune response, with no evidence for Th1-immune-mediated collateral tissue damage. Furthermore, mice previously infected with the plasmid-deficient strains are protected against oviduct disease upon challenge with virulent C. muridarum. If plasmid-cured derivatives of human C. trachomatis biovars exhibit similar phenotypic characteristics, they have the potential to serve as vaccines to prevent human disease. 相似文献
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An inclusion membrane protein from Chlamydia trachomatis enters the MHC class I pathway and stimulates a CD8+ T cell response 总被引:5,自引:0,他引:5
Starnbach MN Loomis WP Ovendale P Regan D Hess B Alderson MR Fling SP 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(9):4742-4749
During its developmental cycle, the intracellular bacterial pathogen Chlamydia trachomatis remains confined within a protective vacuole known as an inclusion. Nevertheless, CD8(+) T cells that recognize Chlamydia Ags in the context of MHC class I molecules are primed during infection. MHC class I-restricted presentation of these Ags suggests that these proteins or domains from them have access to the host cell cytoplasm. Chlamydia products with access to the host cell cytoplasm define a subset of molecules uniquely positioned to interface with the intracellular environment during the pathogen's developmental cycle. In addition to their use as candidate Ags for stimulating CD8(+) T cells, these proteins represent novel candidates for therapeutic intervention of infection. In this study, we use C. trachomatis-specific murine T cells and an expression-cloning strategy to show that CT442 from Chlamydia is targeted by CD8(+) T cells. CT442, also known as CrpA, is a 15-kDa protein of undefined function that has previously been shown to be associated with the Chlamydia inclusion membrane. We show that: 1) CD8(+) T cells specific for an H-2D(b)-restricted epitope from CrpA are elicited at a significant level (approximately 4% of splenic CD8(+) T cells) in mice in response to infection; 2) the response to this epitope correlates with clearance of the organism from infected mice; and 3) immunization with recombinant vaccinia virus expressing CrpA elicits partial protective immunity to subsequent i.v. challenge with C. trachomatis. 相似文献
14.
S K Kim M Angevine K Demick L Ortiz R Rudersdorf D Watkins R DeMars 《Journal of immunology (Baltimore, Md. : 1950)》1999,162(11):6855-6866
HLA class I-restricted CD8+ CTLs specific for the major outer membrane protein (MOMP) of Chlamydia trachomatis are present in the peripheral blood of humans who acquired genital tract infections with the organism. Three HLA-A2-restricted epitopes and two HLA-B51-restricted epitopes were identified in serovar E-MOMP. One of the five epitopes spans a variable segment of MOMP and is likely a serovar E-specific epitope. The other four epitopes are localized in constant segments and are C. trachomatis species specific. CTL populations specific for one or more of the four constant segment epitopes were isolated from all 10 infected subjects tested, regardless of infecting serovars, but from only one of seven uninfected subjects tested. The CTLs failed to recognize corresponding peptides derived from Chlamydia pneumoniae MOMP, further suggesting that they indeed resulted from genital tract infections with C. trachomatis. Significantly, ME180 human cervical epithelial cells productively infected with C. trachomatis were killed by the MOMP peptide-specific CTLs. Further investigations of the ability of such CTLs to lyse normal infected epithelial cells and their presence at inflamed sites in the genital tract will help understand the protective or pathological role of CTLs in chlamydial infections. The MOMP CTL epitopes may be explored as potential components of a subunit vaccine against sexually transmitted diseases caused by C. trachomatis. Moreover, the knowledge provided here will facilitate studies of HLA class I pathways of chlamydial Ag processing and presentation in physiologically relevant human APCs. 相似文献
15.
Wang H Zhao L Peng Y Liu J Qi M Chen Q Yang X Zhao W 《FEMS immunology and medical microbiology》2012,65(1):43-54
Natural killer T (NKT) cells are a unique lymphocyte subpopulation which has an important role in the response to microbial pathogens. In this study, we used α-galactosylceramide (α-GalCer), a specific ligand of NKT cells, to enhance NKT response and examine its effect on host defense against genital tract Chlamydia muridarum infection. The results showed that α-GalCer treatment before infection led to reduced pathological changes and bacterial burden in the genital tract. Moreover, α-GalCer-treated mice showed greater local Th1 cytokine production [interferon γ (IFN-γ) and interleukin 12 (IL-12)] in local lymph node cells and genital tissues following challenge infection compared with untreated mice, as well as an enhanced level of IFN-γ production by NK and T cells. In addition, NKT cells in the mice with genital tract C. muridarum infection, unlike those from na?ve mice, showed a polarized IFN-γ production. These results suggest a promoting role of NKT cells on type 1 T cell immune response and host resistance to Chlamydia in genital tract infection. 相似文献
16.
Cell-mediated immunity (CMI) is key to defense against intracellular pathogens such as Chlamydia trachomatis and viruses that infect the lower female genital tract, but little is known about CMI at this site. Recent studies indicate that there are immunological microenvironments within the female genital tract, and that immune functions are affected by hormones as well as infections and inflammatory processes. To determine the distribution of mediators of CMI within the lower female genital tract, we have enumerated and characterized T-lymphocyte subsets and natural killer and antigen presenting cells (APCs; macrophages and dendritic cells) in the introitus, vagina, ectocervix, endocervix and cervical transformation zone (TZ) from healthy women, and have examined the effects of the menstrual cycle, menopause and inflammation on these parameters. In women without inflammation, T cells and APCs were most prevalent in the cervical TZ and surrounding tissue. Intraepithelial lymphocytes were predominantly CD8+ T cell+; most CD8+ cells in the TZ and endocervix, and a proportion of cells in the ectocervix, expressed T-cell internal antigen-1, a marker of cytotoxic potential. In contrast, the normal vaginal mucosa contained few T cells and APCs. Cervicitis and vaginitis cases had increased numbers of intraepithelial CD8+ and CD4+ lymphocytes and APCs. The menstrual cycle and menopause had no apparent effect on cellular localization or abundance in any of the lower genital tract tissues. These data indicate that the cervix, especially the TZ, is the major inductive and effector site for CMI in the lower female genital tract. Because CD4+ T cells and APCs are primary host cells for human immunodeficiency virus type 1 (HIV-1), these data also provide further evidence that the cervix is a primary infection site of HIV-1, and that inflammation increases the risk of HIV transmission. 相似文献
17.
Gervassi AL Probst P Stamm WE Marrazzo J Grabstein KH Alderson MR 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(8):4278-4286
CD8(+) T cells are a key immune component for the eradication of many intracellular pathogens. This study aims to characterize the human CD8(+) T cell response to naturally processed chlamydial Ags in individuals exposed to the intracellular pathogen Chlamydia trachomatis. By using C. trachomatis-infected autologous dendritic cells (DCs) as stimulators, Chlamydia-reactive CD8(+) T cell responses were detected in all 10 individuals tested. The majority of the Chlamydia-reactive CD8(+) T cells were non-MHC class Ia restricted in all three of the individuals tested. From one donor, three non-class Ia-restricted and two class Ia-restricted Chlamydia-specific CD8(+) T cells were cloned and characterized further. All five T cell clones secreted IFN-gamma in response to autologous DCs infected with viable Chlamydia, but not with DCs pulsed with inactivated chlamydial elementary bodies. MHC class Ia-restricted and non-class Ia-restricted responses were inhibited by DC treatment with a proteasomal inhibitor and an endoplasmic reticulum-Golgi transport inhibitor, suggesting that these T cells recognize a peptide Ag translocated to the host cell cytosol during infection that is processed via the classical class Ia Ag-processing pathway. Even though both restricted and nonrestricted CD8(+) T cells produced IFN-gamma in response to Chlamydia-infected fibroblasts, only the non-class Ia-restricted cells were lytic for these targets. The class Ia-restricted CTLs, however, were capable of cytolysis as measured by redirected killing. Collectively, these data demonstrate that both class Ia-restricted and non-classically restricted CD8(+) T cells are elicited in C. trachomatis-exposed individuals. Their role in host immunity remains to be elucidated. 相似文献
18.
沙眼衣原体是引起沙眼和泌尿生殖道感染的主要病原体。据世界卫生组织2015年统计,全球每年约有1.3亿沙眼衣原体感染新发病例。研究表明CD4^+Th1型细胞免疫应答在抵抗沙眼衣原体感染中发挥着重要作用。因此,研究者依照抗沙眼衣原体感染的免疫应答特点,构建出许多候选疫苗,但都没有成功地应用于临床。近年研究发现,生殖道黏膜组织不仅存在体液免疫和细胞免疫,还驻留着一些引人注目的免疫细胞,提示增强黏膜免疫可作为预防沙眼衣原体感染的潜在途径,是抵抗生殖道沙眼衣原体感染的免疫新策略。本文全面概述了黏膜免疫与女性生殖道沙眼衣原体感染的研究进展,并为今后研制沙眼衣原体疫苗提供一些建议。 相似文献
19.
A better understanding of the regulatory role of genital tract T cells is much needed. In this study, we have analyzed the phenotype, distribution, and function of T lymphocytes in the female genital tract of naive, pregnant, or Chlamydia trachomatis-infected C57BL/6 mice. Unexpectedly, we found that the dominant lymphocyte population (70-90%) in the genital tract was that of CD3(+)alphabetaTCR(int)CD4(-)CD8(-) T cells. Moreover, these cells were CD90(low) but negative for the classical T cell markers CD2 and CD5. The CD3(+)B220(low) cells were NK1.1 negative and found in nude mice as well as in mice deficient for MHC class II, beta(2)-microglobulin, and CD1, indicating extrathymic origin. They dominated the KJ126(+)Vbeta8.2(+) population in the genital tract of DO11.10 OVA TCR-transgenic mice, further supporting the idea that the CD3(+)B220(low) cells are truly T cells. The function of these T cells appeared not to be associated with immune protection, because only CD4(+) and CD8(+) T cells increased in the genital tract following chlamydial infection. Notwithstanding this, the infected, as well as the uninfected and the pregnant, uterus was dominated by a high level of the CD3(+)CD4(-)CD8(-)B220(low) cells. Following in vitro Ag or polyclonal stimulation of the CD3(+)CD4(-)CD8(-)B220(low) cells, poor proliferative responses were observed. However, these cells strongly impaired splenic T cell proliferation in a cell density-dependent manner. A large fraction of the cells expressed CD25 and produced IFN-gamma upon anti-CD3 plus anti-CD28 stimulation, arguing for a strong regulatory role of this novel T cell population in the mouse female genital tract. 相似文献
20.
Steele LN Balsara ZR Starnbach MN 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(10):6327-6337
Chlamydia trachomatis is a global human pathogen causing diseases ranging from blinding trachoma to pelvic inflammatory disease. To explore how innate and adaptive immune responses cooperate to protect against systemic infection with C. trachomatis L2, we investigated the role of macrophages (Mphi) and dendritic cells (DCs) in the stimulation of C. trachomatis-specific CD8(+) T cells. We found that C. trachomatis infection of Mphi and DCs is far less productive than infection of nonprofessional APCs, the typical targets of infection. However, despite the limited replication of C. trachomatis within Mphi and DCs, infected Mphi and DCs process and present C. trachomatis CD8(+) T cell Ag in a proteasome-dependent manner. These findings suggest that although C. trachomatis is a vacuolar pathogen, some Ags expressed in infected Mphi and DCs are processed in the host cell cytosol for presentation to CD8(+) T cells. We also show that even though C. trachomatis replicates efficiently within nonprofessional APCs both in vitro and in vivo, Ag presentation by hematopoietic cells is essential for initial stimulation of C. trachomatis-specific CD8(+) T cells. However, when DCs infected with C. trachomatis ex vivo were adoptively transferred into naive mice, they failed to prime C. trachomatis-specific CD8(+) T cells. We propose a model for priming C. trachomatis-specific CD8(+) T cells whereby DCs acquire C. trachomatis Ag by engulfing productively infected nonprofessional APCs and then present the Ag to T cells via a mechanism of cross-presentation. 相似文献