Project description:BACKGROUND:Sexual transmission rates of Chlamydia trachomatis (Ct) cannot be measured directly; however, the study of concordance of Ct infection in sexual partnerships (dyads) can help to illuminate factors influencing Ct transmission. METHODS:Heterosexual men and women with Ct infection and their sex partners were enrolled and partner-specific coital and behavioral data collected for the prior 30 days. Microbiological data included Ct culture, and nucleic acid amplification testing (NAAT), quantitative Ct polymerase chain reaction, and ompA genotyping. We measured Ct concordance in dyads and factors (correlates) associated with concordance. RESULTS:One hundred twenty-one women and 125 men formed 128 dyads. Overall, 72.9% of male partners of NAAT-positive women and 68.6% of female partners of NAAT-positive men were Ct-infected. Concordance was more common in dyads with culture-positive members (78.6% of male partners, 77% of female partners). Partners of women and men who were NAAT-positive only had lower concordance (33.3%, 46.4%, respectively). Women in concordant dyads had significantly higher median endocervical quantitative Ct polymerase chain reaction values (3,032) compared with CT-infected women in discordant dyads (1013 inclusion forming units DNA equivalents per mL; P < 0.01). Among 54 Ct-concordant dyads with ompA genotype data for both members, 96.2% had identical genotypes. CONCLUSIONS:Higher organism load appears associated with concordance among women. Same-genotype chlamydial concordance was high in sexual partnerships. No behavioral factors were sufficiently discriminating to guide partner services activities. Findings may help model coitus-specific transmission probabilities.
Project description:The advent of high-throughput technologies, such as 16s rDNA sequencing, has significantly contributed to expanding our knowledge of the microbiota composition of the genital tract during infections such as Chlamydia trachomatis. The growing body of metagenomic data can be further exploited to provide a functional characterization of microbial communities via several powerful computational approaches. Therefore, in this study, we investigated the predicted metabolic pathways of the cervicovaginal microbiota associated with C. trachomatis genital infection in relation to the different Community State Types (CSTs), via PICRUSt2 analysis. Our results showed a more rich and diverse mix of predicted metabolic pathways in women with a CST-IV microbiota as compared to all the other CSTs, independently from infection status. C. trachomatis genital infection further modified the metabolic profiles in women with a CST-IV microbiota and was characterized by increased prevalence of the pathways for the biosynthesis of precursor metabolites and energy, biogenic amino-acids, nucleotides, and tetrahydrofolate. Overall, predicted metabolic pathways might represent the starting point for more precisely designed future metabolomic studies, aiming to investigate the actual metabolic pathways characterizing C. trachomatis genital infection in the cervicovaginal microenvironment.
Project description:Chlamydia spp. productively infect mucosal epithelial cells of multiple anatomical sites, including the conjunctiva, lungs, gastrointestinal (GI) tract, and urogenital tract. We, and others, previously established that chlamydial GI tropism is mediated by distinct chromosomal and plasmid factors. In this study, we describe a genital infection-attenuated Chlamydia muridarum mutant (GIAM-1) that is profoundly and specifically attenuated in the murine genital tract. GIAM-1 infected the murine GI tract similarly to wild-type (WT) Chlamydia muridarum but did not productively infect the lower genital tract of female mice, ascend to infect the upper genital tract, or cause hydrosalpinx. However, GI infection of mice with GIAM-1 elicited a transmucosal immune response that protected against subsequent genital challenge with WT Chlamydia muridarum Collectively, our results demonstrate that chlamydia mutants that are profoundly attenuated for specific organ tissues can be derived and demonstrate that live-attenuated vaccine strains that infect the GI tract, but do not elicit genital tract disease, could be used to protect against chlamydia genital tract infection and disease.IMPORTANCE Chlamydia is the most common sexually transmitted bacterial infection in the United States. Most chlamydia genital infections resolve without serious consequences; however, untreated infection in women can cause pelvic inflammatory disease and infertility. Antibiotics are very effective in treating chlamydia, but most genital infections in both men and women are asymptomatic and go undiagnosed. Therefore, there is a critical need for an effective vaccine. In this work, we show that a mutant chlamydia strain, having substantially reduced virulence for genital infection, colonizes the gastrointestinal tract and produces robust immunity to genital challenge with fully virulent wild-type chlamydia. These results are an important advance in understanding chlamydial virulence and provide compelling evidence that safe and effective live-attenuated chlamydia vaccines may be feasible.
Project description:Defining the mechanisms of immunity conferred by the combination of antibody and CD4+ T cells is fundamental to designing an efficacious chlamydial vaccine. Using the Chlamydia muridarum genital infection model of mice, which replicates many features of human C. trachomatis infection and avoids the characteristic low virulence of C. trachomatis in the mouse, we previously demonstrated a significant role for antibody in immunity to chlamydial infection. We found that antibody alone was not protective. Instead, protection appeared to be conferred through an undefined antibody-cellular interaction. Using gene knockout mice and in vivo cellular depletion methods, our data suggest that antibody-mediated protection is dependent on the activation of an effector cell population in genital tract tissues by CD4+ T cells. Furthermore, the CD4+ T cell-secreted cytokine interferon-gamma (IFN?) was found to be a key component of the protective antibody response. The protective function of IFN? was not related to the immunoglobulin class or magnitude of the Chlamydia-specific antibody response or to recruitment of an effector cell population to genital tract tissue. Rather, IFN? appears to be necessary for activation of the effector cell population that functions in antibody-mediated chlamydial immunity. Our results confirm the central role of antibody in immunity to chlamydia reinfection, and demonstrate a key function for IFN? in antibody-mediated protection.
Project description:The T cell response to Chlamydia genital tract infections in humans and mice is unusual in that the majority of antigen-specific CD8 T cells are not restricted by HLA/MHC class I and therefore have been referred to as “unrestricted” or “atypical”. We previously reported that a subset of unrestricted murine Chlamydia-specific CD8 T cells had an unusual cytokine polarization pattern that included IFN-ɣ and IL-13. For this report, we investigated the transcriptome of Chlamydia-specific CD8ɣ13 T cells, comparing them to Chlamydia-specific multifunctional Tc1 clones using gene expression micro array analysis. The molecular study revealed that CD8ɣ13 polarization included IL-5 in addition to IFN-γ and IL-13. Adoptive transfer studies were performed with Tc1 clone and CD8ɣ13 T cell clones to determine whether either influenced bacterial clearance or immunopathology during Chlamydia muridarum (Cm) genital tract infections. To our surprise, an adoptively transferred CD8ɣ13 T cell clone was remarkably proficient at preventing chlamydia immunopathology while the multifunctional Tc1 clone did not enhance clearance or significantly protect from immunopathology. Mapping studies with MHC class I- and class II-deficient splenocytes showed our previously published Chlamydia-specific CD8 T cell clones are MHC class II-restricted. MHC class II-restricted CD8 T cells may play important roles in protection from intracellular pathogens that limit class I antigen presentation or deplete the CD4 T cell compartment.
Project description:Chlamydia trachomatis is an obligate intracellular Gram-negative bacterium that frequently causes an asymptomatic genital tract infection, gradually cleared by host immunity Transcriptome profiles were made of endometrial tissue from women with or without genital tract C. trachomatis infection, to characterize host responses to infection. Profiles showed that infection polarized host defense toward Type 2 immune responses. Responses included fibrin deposition, enhanced wound repair, and tissue remodeling.
Project description:Some members of the genus Chlamydia, including the human pathogen Chlamydia trachomatis, infect multiple tissues, including the genital and gastrointestinal (GI) tracts. However, it is unknown if bacterial targeting to these sites is mediated by multifunctional or distinct chlamydial factors. We previously showed that disruption of individual large clostridial toxin homologs encoded within the Chlamydia muridarum plasticity zone were not critical for murine genital tract infection. Here, we assessed whether cytotoxin genes contribute to C. muridarum GI tropism. Infectivity and shedding of wild-type (WT) C. muridarum and three mutants containing nonsense mutations in different cytotoxin genes, tc0437, tc0438, and tc0439, were compared in mouse genital and GI infection models. One mutant, which had a nonsense mutation in tc0439, was highly attenuated for GI infection and had a GI 50% infectious dose (ID50) that was 1,000 times greater than that of the WT. GI inoculation with this mutant failed to elicit anti-chlamydial antibodies or to protect against subsequent genital tract infection. Genome sequencing of the tc0439 mutant revealed additional chromosomal mutations, and phenotyping of additional mutants suggested that the GI attenuation might be linked to a nonsense mutation in tc0600 The molecular mechanism underlying this dramatic difference in tissue-tropic virulence is not fully understood. However, isolation of these mutants demonstrates that distinct chlamydial chromosomal factors mediate chlamydial tissue tropism and provides a basis for vaccine initiatives to isolate chlamydia strains that are attenuated for genital infection but retain the ability to colonize the GI tract and elicit protective immune responses.
Project description:BackgroundEstimating prevalence of Chlamydia trachomatis (CT) worldwide is necessary in designing control programs and allocating health resources. We performed a meta-analysis to calculate the prevalence of CT in the general population.MethodsThe Pubmed and Embase databases were searched for eligible population-based studies from its inception through June 5, 2019. Q test and I2 statistic were used to calculate the heterogeneity between studies. Random effects models were used to pool the prevalence of CT. Meta regression was performed to explore the possible sources of heterogeneity. Publication bias was evaluated using a funnel plot and "trim and fill" method.ResultsTwenty nine studies that reported prevalence of CT infection from 24 countries were identified, including a total population of 89,886 persons. The pooled prevalence of CT among the general population was 2.9% (95% CI, 2.4-3.5%), and females had a higher CT prevalence (3.1, 95% CI, 2.5-3.8%) than males (2.6, 95% CI, 2.0-3.2%) (χ2 = 10.38, P < 0.01). Prevalence of CT was highest in region of America (4.5, 95% CI, 3.1-5.9%), especially in Latin America (6.7, 95% CI, 5.0-8.4%), followed by females in region of Africa (3.8, 95% CI, 0.7-6.9%), while South-East Asia had a lowest CT prevalence 0.8% (95% CI, 0.3-1.3%).ConclusionsThis study provided the updated prevalence of CT among general population worldwide. General population from Latin America, especially females, and women in Africa should be given priority by WHO when design and delivery CT control programs.
Project description:Chlamydia trachomatis is an obligate intracellular Gram-negative bacterium that frequently causes an asymptomatic genital tract infection, gradually cleared by host immunity Transcriptome profiles were made of endometrial tissue from women with or without genital tract C. trachomatis infection, to characterize host responses to infection. Profiles showed that infection polarized host defense toward Type 2 immune responses. Responses included fibrin deposition, enhanced wound repair, and tissue remodeling. Trans-cervical endometrial biopsy specimens were collected from 10 women with no identified upper or lower genital tract infection and 12 women with C. trachomatis endometrial infection.