Abstract
Pelvic inflammatory disease (PID) results from ascension of sexually transmitted pathogens from the lower genital tract to the uterus and/or fallopian tubes in women, with potential spread ...to neighboring pelvic organs. Patients may present acutely with lower abdominal or pelvic pain and pelvic organ tenderness. Many have subtle symptoms or are asymptomatic and present later with tubal factor infertility, ectopic pregnancy, or chronic pelvic pain. Neisseria gonorrhoeae and Chlamydia trachomatis are the 2 most commonly recognized PID pathogens. Their ability to survive within host epithelial cells and neutrophils highlights a need for T-cell–mediated production of interferon γ in protection. Data indicate that for both pathogens, antibody can accelerate clearance by enhancing opsonophagocytosis and bacterial killing when interferon γ is present. A study of women with N. gonorrhoeae– and/or C. trachomatis–induced PID with histologic endometritis revealed activation of myeloid cell, cell death, and innate inflammatory pathways in conjunction with dampening of T-cell activation pathways. These findings are supported by multiple studies in mouse models of monoinfection with N. gonorrhoeae or Chlamydia spp. Both pathogens exert multiple mechanisms of immune evasion that benefit themselves and each other at the expense of the host. However, similarities in host immune mechanisms that defend against these 2 bacterial pathogens instill optimism for the prospects of a combined vaccine for prevention of PID and infections in both women and men.
is the most common sexually transmitted bacterial pathogen in the world. Antibiotic treatment does not prevent against reinfection and a vaccine is not yet available.
We focus the review on the ...progress made of our understanding of the immunological responses required for a vaccine to elicit protection, and on the antigens, adjuvants, routes of immunization and delivery systems that have been tested in animal models. PubMed and Google Scholar were used to search publication on these topics for the last 5 years and recent Reviews were examined.
The first Phase 1 clinical trial of a
vaccine to protect against genital infections was successfully completed. We expect that, in the next five years, additional vaccine clinical trials will be implemented.
Chlamydia trachomatis is the most common cause of sexually transmitted bacterial infection globally. These infections translate to a significant public health burden, particularly women's healthcare ...costs due to serious disease sequelae such as pelvic inflammatory disease (PID), tubal factor infertility, chronic pelvic pain, and ectopic pregnancy. There is no evidence that natural immunity can provide complete, long-term protection necessary to prevent chronic pathology, making human vaccine development critical. Vaccine design will require careful consideration of protective versus pathological host-response mechanisms in concert with elucidation of optimal antigens and adjuvants. Evidence suggests that a Th1 response, facilitated by IFN-γ-producing CD4 T cells, will be instrumental in generating long-term, sterilizing immunity. Although the role of antibodies is not completely understood, they have exhibited a protective effect by enhancing chlamydial clearance. Future work will require investigation of broadly neutralizing antibodies and antibody-augmented cellular immunity to successfully design a vaccine that potently elicits both arms of the immune response. Sterilizing immunity is the ultimate goal. However, vaccine-induced partial immunity that prevents upper genital tract infection and inflammation would be cost-effective compared to current screening and treatment strategies. In this chapter, we examine evidence from animal and human studies demonstrating protective adaptive immune responses to Chlamydia and discuss future challenges and prospects for vaccine development.
Oropharyngeal candidiasis (OPC), caused by the commensal fungus Candida albicans, is an opportunistic infection associated with infancy, AIDS, and IL-17-related primary immunodeficiencies. The ...Th17-associated cytokines IL-23 and IL-17 are crucial for immunity to OPC, but the mechanisms by which they mediate immunity are poorly defined. IL-17RA-deficient humans and mice are strongly susceptible to OPC, with reduced levels of CXC chemokines and concomitantly impaired neutrophil recruitment to the oral mucosa. Paradoxically, humans with isolated neutropenia are typically not susceptible to candidiasis. To determine whether immunity to OPC is mediated via neutrophil recruitment, mice lacking CXCR2 were subjected to OPC and were found to be highly susceptible, although there was no dissemination of fungi to peripheral organs. To assess whether the entire neutrophil response is IL-17 dependent, IL-17RA(-/-) and IL-23(-/-) mice were administered neutrophil-depleting Abs and subjected to OPC. These mice displayed increased oral fungal burdens compared with IL-17RA(-/-) or IL-23(-/-) mice alone, indicating that additional IL-17-independent signals contribute to the neutrophil response. WT mice treated with anti-Gr-1 Abs exhibited a robust infiltrate of CD11b(+)Ly-6G(low)F4/80(-) cells to the oral mucosa but were nonetheless highly susceptible to OPC, indicating that this monocytic influx is insufficient for host defense. Surprisingly, Ly-6G Ab treatment did not induce the same strong susceptibility to OPC in WT mice. Thus, CXCR2(+) and Gr-1(+) neutrophils play a vital role in host defense against OPC. Moreover, defects in the IL-23/17 axis cause a potent but incomplete deficiency in the neutrophil response to oral candidiasis.
Plasmid-mediated virulence in Chlamydia Turman, Breanna J.; Darville, Toni; O'Connell, Catherine M.
Frontiers in cellular and infection microbiology,
08/2023, Letnik:
13
Journal Article
Recenzirano
Odprti dostop
Chlamydia trachomatis
infection of ocular conjunctiva can lead to blindness, while infection of the female genital tract can lead to chronic pelvic pain, ectopic pregnancy, and/or infertility. ...Conjunctival and fallopian tube inflammation and the resulting disease sequelae are attributed to immune responses induced by chlamydial infection at these mucosal sites. The conserved chlamydial plasmid has been implicated in enhancing infection, via improved host cell entry and exit, and accelerating innate inflammatory responses that lead to tissue damage. The chlamydial plasmid encodes eight open reading frames, three of which have been associated with virulence: a secreted protein, Pgp3, and putative transcriptional regulators, Pgp4 and Pgp5. Although Pgp3 is an important plasmid-encoded virulence factor, recent studies suggest that chlamydial plasmid-mediated virulence extends beyond the expression of Pgp3. In this review, we discuss studies of genital, ocular, and gastrointestinal infection with
C. trachomatis
or
C. muridarum
that shed light on the role of the plasmid in disease development, and the potential for tissue and species-specific differences in plasmid-mediated pathogenesis. We also review evidence that plasmid-associated inflammation can be independent of bacterial burden. The functions of each of the plasmid-encoded proteins and potential molecular mechanisms for their role(s) in chlamydial virulence are discussed. Although the understanding of plasmid-associated virulence has expanded within the last decade, many questions related to how and to what extent the plasmid influences chlamydial infectivity and inflammation remain unknown, particularly with respect to human infections. Elucidating the answers to these questions could improve our understanding of how chlamydia augment infection and inflammation to cause disease.
We previously demonstrated that plasmid-deficient Chlamydia muridarum retains the ability to infect the murine genital tract but does not elicit oviduct pathology because it fails to activate ...Toll-like receptor 2 (TLR2). We derived a plasmid-cured derivative of the human genital isolate Chlamydia trachomatis D/UW-3/Cx, strain CTD153, which also fails to activate TLR2, indicating this virulence phenotype is associated with plasmid loss in both C. trachomatis and C. muridarum. As observed with plasmid-deficient C. muridarum, CTD153 displayed impaired accumulation of glycogen within inclusions. Transcriptional profiling of the plasmid-deficient strains by using custom microarrays identified a conserved group of chromosomal loci, the expression of which was similarly controlled in plasmid-deficient C. muridarum strains CM972 and CM3.1 and plasmid-deficient C. trachomatis CTD153. However, although expression of glycogen synthase, encoded by glgA, was greatly reduced in CTD153, it was unaltered in plasmid-deficient C. muridarum strains. Thus, additional plasmid-associated factors are required for glycogen accumulation by this chlamydial species. Furthermore, in C. trachomatis, glgA and other plasmid-responsive chromosomal loci (PRCLs) were transcriptionally responsive to glucose limitation, indicating that additional regulatory elements may be involved in the coordinated expression of these candidate virulence effectors. Glucose-limited C. trachomatis displayed reduced TLR2 stimulation in an in vitro assay. During human chlamydial infection, glucose limitation may decrease chlamydial virulence through its effects on plasmid-responsive chromosomal genes.
Interleukin 17 (IL-17) contributes to development of Th1 immunity and neutrophil influx during Chlamydia muridarum pulmonary infection, but its role during C. muridarum genital tract infection has ...not been described. We detected similar numbers of Chlamydia-specific Th17 and Th1 cells in iliac nodes of wild-type mice early during genital C. muridarum infection, while Th1 cells predominated later. il17ra⁻/⁻ mice exhibited a reduced chlamydia-specific Th1 response in draining iliac nodes and decreased local IFN-γ production. Neutrophil influx into the genital tract was also decreased. However, il17ra⁻/⁻ mice resolved infection normally, and no difference in pathology was observed compared to the wild type. Macrophage influx and tumor necrosis factor alpha (TNF-α) production were increased in il17ra⁻/⁻ mice, providing a compensatory mechanism to effectively control chlamydial genital tract infection despite a reduced Th1 response. In ifnγ⁻/⁻ mice, a marked increase in cellular infiltrates and chronic pathology was associated with an increased Th17 response. Although neutralization of IL-17 in ifnγ⁻/⁻ mice decreased neutrophil influx, macrophage infiltration remained intact and the bacterial burden was not increased. Collectively, these results indicate that IL-17 contributes to the generation of Th1 immunity and neutrophil recruitment but is not required for macrophage influx or normal resolution of C. muridarum genital infection. These data highlight the redundant immune mechanisms operative at this mucosal site and the importance of examining site-specific responses to mucosal pathogens.
Identify genetic loci of enhanced susceptibility to
upper genital tract infection in women.
We performed an integrated analysis of DNA genotypes and blood-derived mRNA profiles from 200
exposed women ...to identify expression quantitative trait loci (eQTL) and determine their association with endometrial chlamydial infection using a mediation test. We further evaluated the effect of a lead eQTL on the expression of
by immune cells from women with genotypes associated with low and high whole blood expression of
, respectively.
We identified
-eQTLs modulating mRNA expression of 81 genes (eGenes) associated with altered risk of ascending infection. In women with endometrial infection, eGenes involved in proinflammatory signaling were upregulated. Downregulated eGenes included genes involved in T cell functions pivotal for chlamydial control. eGenes encoding molecules linked to metabolism of tryptophan, an essential chlamydial nutrient, and formation of epithelial tight junctions were also downregulated in women with endometrial infection. A lead eSNP rs10902226 was identified regulating
, a tetrospanin molecule important for immune cell adhesion and migration and T cell proliferation. Further
experiments showed that women with a CC genotype at rs10902226 had reduced rates of endometrial infection with increased
expression in whole blood and T cells when compared to women with a GG genotype.
We discovered genetic variants associated with altered risk for
ascension. A lead eSNP for
is a candidate genetic marker for enhanced CD4 T cell function and reduced susceptibility.
We developed a reusable and open-source machine learning (ML) pipeline that can provide an analytical framework for rigorous biomarker discovery. We implemented the ML pipeline to determine the ...predictive potential of clinical and immunoproteome antibody data for outcomes associated with Chlamydia trachomatis (
) infection collected from 222 cis-gender females with high
exposure. We compared the predictive performance of 4 ML algorithms (naive Bayes, random forest, extreme gradient boosting with linear booster xgbLinear, and
-nearest neighbors KNN), screened from 215 ML methods, in combination with two different feature selection strategies, Boruta and recursive feature elimination. Recursive feature elimination performed better than Boruta in this study. In prediction of
ascending infection, naive Bayes yielded a slightly higher median value of are under the receiver operating characteristic curve (AUROC) 0.57 (95% confidence interval CI, 0.54 to 0.59) than other methods and provided biological interpretability. For prediction of incident infection among women uninfected at enrollment, KNN performed slightly better than other algorithms, with a median AUROC of 0.61 (95% CI, 0.49 to 0.70). In contrast, xgbLinear and random forest had higher predictive performances, with median AUROC of 0.63 (95% CI, 0.58 to 0.67) and 0.62 (95% CI, 0.58 to 0.64), respectively, for women infected at enrollment. Our findings suggest that clinical factors and serum anti-
protein IgGs are inadequate biomarkers for ascension or incident
infection. Nevertheless, our analysis highlights the utility of a pipeline that searches for biomarkers and evaluates prediction performance and interpretability.
Biomarker discovery to aid early diagnosis and treatment using machine learning (ML) approaches is a rapidly developing area in host-microbe studies. However, lack of reproducibility and interpretability of ML-driven biomarker analysis hinders selection of robust biomarkers that can be applied in clinical practice. We thus developed a rigorous ML analytical framework and provide recommendations for enhancing reproducibility of biomarkers. We emphasize the importance of robustness in selection of ML methods, evaluation of performance, and interpretability of biomarkers. Our ML pipeline is reusable and open-source and can be used not only to identify host-pathogen interaction biomarkers but also in microbiome studies and ecological and environmental microbiology research.
PDF
