Immune-mediated control of Chlamydia infection

Roan, Nadia R.; Starnbach, Michael N.

doi:10.1111/j.1462-5822.2007.01069.x

Cited by 71 publications

(87 citation statements)

References 101 publications

(68 reference statements)

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“…Because cell-mediated immunity is a strong component of antichlamydial immune responses (as reviewed in ref. 41), we postulate that inhibitors that target LOS biosynthesis may enhance such responses by allowing limited bacterial replication and antigen presentation, while preventing the spread of infectious particles. Future experiments will be aimed at determining if infected animals treated with LpxC inhibitors can elicit long-term immunity to subsequent chlamydial challenges.…”

Section: Discussionmentioning

confidence: 99%

Lipooligosaccharide is required for the generation of infectious elementary bodies in Chlamydia trachomatis

Nguyen

Cunningham

Liang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Lipopolysaccharides (LPS) and lipooligosaccharides (LOS) are the main lipid components of bacterial outer membranes and are essential for cell viability in most Gram-negative bacteria. Here we show that small molecule inhibitors of LpxC [UDP-3- O -( R -3-hydroxymyristoyl)-GlcNAc deacetylase], the enzyme that catalyzes the first committed step in the biosynthesis of lipid A, block the synthesis of LOS in the obligate intracellular bacterial pathogen Chlamydia trachomatis . In the absence of LOS, Chlamydia remains viable and establishes a pathogenic vacuole (“inclusion”) that supports robust bacterial replication. However, bacteria grown under these conditions were no longer infectious. In the presence of LpxC inhibitors, replicative reticulate bodies accumulated in enlarged inclusions but failed to express selected late-stage proteins and transition to elementary bodies, a Chlamydia developmental form that is required for invasion of mammalian cells. These findings suggest the presence of an outer membrane quality control system that regulates Chlamydia developmental transition to infectious elementary bodies and highlights the potential application of LpxC inhibitors as unique class of antichlamydial agents.

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Section: Discussionmentioning

confidence: 99%

Lipooligosaccharide is required for the generation of infectious elementary bodies in Chlamydia trachomatis

Nguyen

Cunningham

Liang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…To address this question, we used the CD4 + T cells adoptive transfer model (16), according to which CD4 + T cells from Chlamydia-infected mice protect naive mice from Chlamydia challenge, and we assessed whether CD4 + /IFN-γ + T cells specific for the newly identified antigens were included in a protective elementary body (EB)-specific CD4 + T-cell line. Because C. muridarum gives a more robust and consistent infection than C. trachomatis in mice and induces immune responses mimicking many aspects of C. trachomatis infection in humans (15,28), we used the C. muridarum instead of the C. trachomatis model for these experiments. This change required us to produce the recombinant forms of the C. muridarum orthologs of the CD4 + Tcell-inducing C. trachomatis antigens (amino acid identity ranging from 32-99%) ( Table S2).…”

mentioning

confidence: 99%

Approach to discover T- and B-cell antigens of intracellular pathogens applied to the design of Chlamydia trachomatis vaccines

Finco

Frigimelica

Buricchi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Natural immunity against obligate and/or facultative intracellular pathogens is usually mediated by both humoral and cellular immunity. The identification of those antigens stimulating both arms of the immune system is instrumental for vaccine discovery. Although high-throughput technologies have been applied for the discovery of antibody-inducing antigens, few examples of their application for T-cell antigens have been reported. We describe how the compilation of the immunome, here defined as the pool of immunogenic antigens inducing T- and B-cell responses in vivo, can lead to vaccine candidates against Chlamydia trachomatis . We selected 120 C. trachomatis proteins and assessed their immunogenicity using two parallel high-throughput approaches. Protein arrays were generated and screened with sera from C. trachomatis -infected patients to identify antibody-inducing antigens. Splenocytes from C. trachomatis -infected mice were stimulated with 79 proteins, and the frequency of antigen-specific CD4 + /IFN-γ + T cells was analyzed by flow cytometry. We identified 21 antibody-inducing antigens, 16 CD4 + /IFN-γ + –inducing antigens, and five antigens eliciting both types of responses. Assessment of their protective activity in a mouse model of Chlamydia muridarum lung infection led to the identification of seven antigens conferring partial protection when administered with LTK63/CpG adjuvant. Protection was largely the result of cellular immunity as assessed by CD4 + T-cell depletion. The seven antigens provided robust additive protection when combined in four-antigen combinations. This study paves the way for the development of an effective anti- Chlamydia vaccine and provides a general approach for the discovery of vaccines against other intracellular pathogens.

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“…In addition, a chlamydial inclusion body forms during in vivo infection in epithelial cells, the inclusion lyses, and a multitude of chlamydia proteins and organisms are released to the mucosa system. These antigens are predominantly detected by the host's immune system, especially the T cell antigens encoded by chlamydia, which would, upon T cell detection, induce a robust host immune response and cause the host to clear the infection [52]. As such, cleavage of these specific T cell antigens would be essential for chlamydial survival.…”

Section: Discussionmentioning

confidence: 99%

“…As such, cleavage of these specific T cell antigens would be essential for chlamydial survival. It is also possible that CPAF cleaves chlamydial T cell antigens and limits their detection by microbial pattern recognition receptors or their processing and displaying on MHC class II molecules as discussed before [52].…”

Section: Discussionmentioning

confidence: 99%

CPAF selectively degrades chlamydial T cell antigens for inhibiting antigen presentation

Zhang

Zhong

Cai

et al. 2017

J Infect Dev Ctries

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Introduction: Chlamydia trachomatis is the leading cause of sexually transmitted bacterial disease, which may cause significant threats, such as pelvic inflammatory disease and tubal factor infertility, to women if untreated. The pathological mechanisms of chlamydia-induced disease remain largely unknown, but it has been proposed that CPAF, a chlamydia-secreted serine protease, may play major roles in aiding chlamydial infection and contribute to chlamydia pathogenesis during in vivo infection. According to previous results, CPAF targets host immunity by degrading antimicrobial peptides and neutralizing complement activity; however, whether CPAF is involved in chlamydial antigen presentation has never been reported. Methodology: Antigen presentation assay was used to monitor the effects of CPAF on OT1-, OT2-, and chlamydia T cell antigen-mediated antigen presentation. In vitro cell-free degradation assay was used to detect CPAF processing of chlamydia T cell antigens. Results: We found that CPAF preferably inhibits OT2-but not OT1-mediated antigen presentation. CPAF inhibits OT2 antigen presentation by direct proteolytic cleavage in the wild type CPAF, but not enzymatic mutants. Importantly, several previously identified chlamydial T cell antigens were selectively degraded by CPAF when co-incubated in vitro. In addition, specific inhibition T cell antigen presentation by CPAF was correlated with T cell antigen cleavage by CPAF in vitro assay. Conclusions: Our experiments demonstrated that CPAF selectively and specifically degrades chlamydial T cell antigens, which chlamydia may utilize as a novel mechanism for evading host immune responses to promote chlamydia survival.

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Immune-mediated control of Chlamydia infection

Cited by 71 publications

References 101 publications

Lipooligosaccharide is required for the generation of infectious elementary bodies in Chlamydia trachomatis

Lipooligosaccharide is required for the generation of infectious elementary bodies in Chlamydia trachomatis

Approach to discover T- and B-cell antigens of intracellular pathogens applied to the design of Chlamydia trachomatis vaccines

CPAF selectively degrades chlamydial T cell antigens for inhibiting antigen presentation

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