Immunization with a Combination of Integral Chlamydial Antigens and a Defined Secreted Protein Induces Robust Immunity against Genital Chlamydial Challenge

Li, Weidang; Murthy, Ashlesh K.; Guentzel, M. Neal; Chambers, James P.; Forsthuber, Thomas G.; Seshu, J.; Zhong, Guangming; Arulanandam, Bernard P.

doi:10.1128/iai.00346-10

Cited by 20 publications

(18 citation statements)

References 36 publications

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“…Vaccination with CPAF can induce a protective response against vaginal challenge, but due to the delayed induction of protection, CPAF may be best utilized in conjunction with another antigen. As such, mice vaccinated with rCPAF plus UV-inactivated EBs and CpG-1826 have a shorter duration of infection than those vaccinated with rCPAF and CpG-1826 alone (50). These mice also began clearing the infection sooner than those vaccinated with rCPAF and CpG-1826 alone (50).…”

Section: Antigensmentioning

confidence: 86%

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Vaccination againstChlamydiaGenital Infection Utilizing the MurineC. muridarumModel

2011

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2Chlamydia trachomatis genital infection is a worldwide public health problem, and considerable effort has been expended on developing an efficacious vaccine. The murine model of C. muridarum genital infection has been extremely useful for identification of protective immune responses and in vaccine development. Although a number of immunogenic antigens have been assessed for their ability to induce protection, the majority of studies have utilized the whole organism, the major outer membrane protein (MOMP), or the chlamydial protease-like activity factor (CPAF). These antigens, alone and in combination with a variety of immunostimulatory adjuvants, have induced various levels of protection against infectious challenge, ranging from minimal to nearly sterilizing immunity. Understanding of the mechanisms of natural infection-based immunity and advances in adjuvant biology have resulted in studies that are increasingly successful, but a vaccine licensed for use in humans has not yet been brought to fruition. Here we review immunity to chlamydial genital infection and vaccine development using the C. muridarum model.Chlamydia trachomatis, a Gram-negative obligate intracellular bacterium with a tropism for mucosal epithelial cells, is the most common cause of bacterial sexually transmitted disease in both developed and developing countries, with more than 90 million new cases occurring each year (113-115). More than 4 million new cases of C. trachomatis infection occur each year in the United States, where costs associated with treating those infections and associated complications are in excess of $2 billion annually (107). In the genital tract, infection with C. trachomatis is propagated within the single-cell columnar layer of the epithelium in the urethra of men and the endocervix of women. Within the epithelial cells, C. trachomatis undergoes a unique biphasic developmental cycle consisting of an infectious, but metabolically inert elementary body (EB) and a noninfectious, but metabolically active reticulate body (RB). After completion of the developmental cycle, the EBs are released and infect neighboring epithelial cells, thereby spreading the infection.Infection can result in acute inflammation characterized by redness, edema, and mucosal discharge and is diagnosed clinically as mucopurulent cervicitis in women and nongonococcal urethritis in men (10, 85). In women, infection can manifest as abnormal vaginal discharge and/or postcoital bleeding, while the infection is limited to the lower genital tract, and irregular uterine bleeding and/or pelvic discomfort once the infection ascends to the upper genital tract (85). Symptoms in males are generally limited to dysuria and moderate clear-to-whitish discharge (85). While these symptoms signify an infection, the absence of such symptoms does not necessarily indicate the absence of infection. It is estimated that Ͼ70% of women and 50% of men experience asymptomatic infections (15,113). Without symptoms providing the impetus, asymptomatic individuals may not seek ...

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Section: Antigensmentioning

confidence: 86%

“…As such, mice vaccinated with rCPAF plus UV-inactivated EBs and CpG-1826 have a shorter duration of infection than those vaccinated with rCPAF and CpG-1826 alone (50). These mice also began clearing the infection sooner than those vaccinated with rCPAF and CpG-1826 alone (50).…”

Section: Antigensmentioning

confidence: 86%

Vaccination againstChlamydiaGenital Infection Utilizing the MurineC. muridarumModel

2011

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“…MHC class I antigen presentation is dispensable for protective host immunity while MHC class II is absolutely required (7). Recent data in experimental mouse models argues for a supportive role for antibodies in vaccine-generated immunity in the genital tract (8, 9). A large body of research has identified CD4 T cells of the Th1 subset as the critical parameter for protective host immunity (6).…”

Section: Introductionmentioning

confidence: 99%

Plac8-Dependent and Inducible NO Synthase-Dependent Mechanisms ClearChlamydia muridarumInfections from the Genital Tract

Johnson

Kerr

Slaven

2012

The Journal of Immunology

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Chlamydia trachomatis urogenital serovars replicate predominately in genital tract epithelium. This tissue tropism poses a unique challenge for host defense and vaccine development. Studies utilizing the Chlamydia muridarum mouse model have shown that CD4 T cells are critical for clearing genital tract infections. In vitro studies have shown that CD4 T cells terminate infection by up regulating epithelial iNOS transcription and nitric oxide production. However, this mechanism is not critical as iNOS-deficient mice clear infections normally. We recently showed that a subset of Chlamydia-specific CD4 T cell clones could terminate replication in epithelial cells using an iNOS-independent mechanism requiring T cell degranulation. We advance that work using microarrays to compare iNOS-dependent and iNOS-independent CD4 T cell clones. Plac8 was differentially expressed by clones having the iNOS-independent mechanism. Plac8-deficient mice had delayed clearance of infection, and Plac8-deficient mice treated with the iNOS-inhibitor N-monomethyl-L-arginine were largely unable to resolve genital tract infections over 8 weeks. These results demonstrate that there are two independent and redundant T cell mechanisms for clearing C. muridarum genital tract infections; one dependent on iNOS, the other dependent on Plac8. While T cells subsets are routinely defined by cytokine profiles, there may be important subdivisions by effector function, in this case CD4Plac8.

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“…However, recombinant MOMP, MOMP synthetic peptides, DNA vaccines encoding MOMP, and the passive transfer of MOMP-specific monoclonal antibodies were only partially effective in protecting experimental animals from subsequent challenge [11–17]. Furthermore, immunization with chlamydial protease-like activity factor (CPAF) [18–20], translocated actin-recruiting phosphoprotein or Tarp [21], and other structural or secreted proteins all showed only partial protection against genital C. trachomatis challenge [22–26]. Given the complex chlamydial organism structures and chlamydial infection biology, it is likely that immunization with combinations of various antigens with each able to induce unique effector mechanisms to simultaneously attack multiple stages of the infection processes may be necessary to achieve a full protection against chlamydial infections and diseases.…”

Section: Introductionmentioning

confidence: 99%

Induction of protective immunity against Chlamydia muridarum intravaginal infection with the chlamydial immunodominant antigen macrophage infectivity potentiator

Peng

et al. 2013

Microbes and Infection

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We previously reported that 5 Chlamydia muridarum antigens reacted with antisera from >90% mice urogenitally infected with C. muridarum and they are TC0660 (ABC transporter or ArtJ), TC0727 (outer membrane complex protein B or OmcB), TC0828 (macrophage infectivity potentiator or MIP), TC0726 (inclusion membrane protein or Inc) & TC0268 (hypothetical protein or HP). The orthologs of these antigens in Chlamydia trachomatis were also highly reactive with antisera from women urogenitally infected with C. trachomatis. In the current study, we evaluated these C. muridarum antigens for their ability to induce protection against a C. muridarum intravaginal challenge infection in mice. We found that only MIP induced the most pronounced protection against C. muridarum infection. The protection correlated well with robust C. muridarum MIP-specific antibody and Th1-dominant T cell responses. The MIP-immunized mice displayed significantly reduced live organism shedding from the lower genital tract and highly attenuated inflammatory pathologies in the upper genital tissues. These results demonstrate that MIP, an immunodominant antigen identified by both human and mouse antisera, may be considered a component of a multi-subunit chlamydial vaccine for inducing protective immunity.

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Immunization with a Combination of Integral Chlamydial Antigens and a Defined Secreted Protein Induces Robust Immunity against Genital Chlamydial Challenge

Cited by 20 publications

References 36 publications

Vaccination againstChlamydiaGenital Infection Utilizing the MurineC. muridarumModel

Vaccination againstChlamydiaGenital Infection Utilizing the MurineC. muridarumModel

Plac8-Dependent and Inducible NO Synthase-Dependent Mechanisms ClearChlamydia muridarumInfections from the Genital Tract

Induction of protective immunity against Chlamydia muridarum intravaginal infection with the chlamydial immunodominant antigen macrophage infectivity potentiator

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