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O'Connell, C. M.

Publications and source records attributed to O'Connell, C. M..

4 recordsLinked to original sources

Mycoplasmal endosymbionts of Trichomonas vaginalis are associated with reduced risk for Chlamydia trachomatis endometrial infection in asymptomatic, coinfected, women.

Trichomonas vaginalis is a protozoan parasite that causes trichomoniasis, the most common curable non-viral sexually transmitted infection, and Chlamydia trachomatis is a bacterial pathogen that can ascend to the upper genital tract and cause pelvic inflammatory disease, infertility, and ectopic pregnancy. T. vaginalis harbors bacterial endosymbionts, including Candidatus Malacoplasma girerdii, an obligate symbiont, and Metamycoplasma hominis, which can live freely or symbiotically. In a 16S rRNA sequencing study of the cervicovaginal microbiome of women at high risk for chlamydial infection, Ca. M. girerdii abundance was one of 13 features predicting lack of chlamydial spread to the endometrium, despite no direct association between T. vaginalis infection and reduced chlamydial ascension. Investigating the relationship between these microorganisms further, we found that T. vaginalis vaginal abundance correlated positively with chlamydial burden in women whose infection was confined to the cervix, while a nonsignificant inverse relationship was seen in women with endometrial spread. Among participants with high chlamydial burden, Ca. M. girerdii was detected exclusively in women without endometrial infection. Both endosymbionts trended toward more frequent detection, and higher abundance, in coinfected women without endometrial spread, while M. hominis abundance correlated strongly with T. vaginalis burden in this group. These findings suggest that mycoplasmal endosymbionts of T. vaginalis, rather than T. vaginalis itself, are microbial factors limiting chlamydial ascension, and point to a three-way interaction between parasite, endosymbiont, and bacterial pathogen that shapes upper genital tract C. trachomatis infection risk.

microbiology↗

miRNA/mRNA analysis of increased TGF-β pathways drive epithelial-mesenchymal transition and regulatory T cell differentiation

Chlamydia trachomatis genital tract infection is linked to severe reproductive complications in women, including ectopic pregnancy, infertility, and adverse pregnancy outcomes. Mouse models of infection suggest that chlamydia-induced dysregulation of microRNAs (miRNAs) can drive harmful cytokine responses, pathogenic epithelial-mesenchymal transition (EMT), and fibrosis. To investigate these mechanisms in humans, we profiled miRNA and mRNA expression in endometrial biopsies from women with endometrial infection (Endo+) and compared them to profiles from women with cervix-only infection (Endo-) or no infection. Ingenuity Pathway Analysis (IPA) revealed that Endo+ tissues had upregulated genes associated with innate and adaptive immune response pathways, as well as EMT regulation, while downregulated genes were linked to cell cycle control. An integrative miRNA-mRNA analysis, which combined a review of published miRNA regulation in human infections and immune responses with IPAs miRNA target filter, identified differentially expressed miRNAs that modulate these pathways in the endometrium of Endo+ women. Functional annotation of these miRNAs showed a predominance of downregulated miRNAs that typically suppress EMT and regulatory T cell (Treg) differentiation, along with miRNAs that usually enhance Th17 responses. Comparisons with previously identified mRNA pathways in blood samples from women with endometrial Chlamydia infection indicated that alterations in TGF-{beta} signaling and EMT were specific to the endometrium. Overall, the miRNA-mRNA interactions inferred from Endo+ tissue suggest increased activity in TGF-{beta} pathways that promote enhanced EMT and Treg differentiation, while reducing Th17 activation. These changes highlight a dual potential for promoting tissue scarring while dampening inflammatory responses that could otherwise limit infection.

genomics↗

Cervicovaginal microbial features predicts Chlamydia trachomatis spread to the upper genital tract of infected women

IntroductionChlamydia trachomatis (CT) infection can lead to pelvic inflammatory disease, infertility and other reproductive sequelae when it ascends to the upper genital tract. Factors including chlamydial burden, co-infection with other sexually-transmitted bacterial pathogens and oral contraceptive use influence risk for upper genital tract spread. Cervicovaginal microbiome composition influences CT susceptibility and we investigated if it contributes to spread by analyzing amplicon sequence variants (ASVs) derived from the V4 region of 16S rRNA genes in vaginal samples collected from women at high risk for CT infection and for whom endometrial infection had been determined. ResultsParticipants were classified as CT negative (CT-, n=77), CT positive at the cervix (Endo-, n=77), or CT positive at both cervix and endometrium (Endo+, n=66). Although we were unable to identify many significant differences between CT infected and uninfected women, differences in abundance of ASVs representing Lactobacillus iners and L. crispatus subspecies but not dominant lactobacilli were detected. Twelve informative ASVs predicted endometrial chlamydial infection (AUC=0.74), with CT ASV abundance emerging as a key predictor. We also observed a positive correlation between levels of cervically secreted cytokines previously associated with CT ascension and abundance of the informative ASVs. ConclusionOur findings suggest that vaginal microbial community members may influence chlamydial spread directly by nutrient limitation and/or disrupting endocervical epithelial integrity and indirectly by modulating pro-inflammatory signaling and/or homeostasis of adaptive immunity. Further investigation of these predictive microbial factors may lead to cervicovaginal microbiome biomarkers useful for identifying women at increased risk for disease.

microbiology↗

Unique T cell signatures are associated with reduced Chlamydia trachomatis reinfection in a highly exposed cohort

Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted infection globally. Understanding natural immunity to CT will inform vaccine design. This study aimed to profile immune cells and associated functional features in CT-infected women, and determine immune profiles associated with reduced risk of ascended endometrial CT infection and CT reinfection. PBMCs from CT-exposed women were profiled by mass cytometry and random forest models identified key features that distinguish outcomes. CT+ participants exhibited higher frequencies of CD4+ Th2, Th17, and Th17 DN CD4 T effector memory (TEM) cells than uninfected participants with decreased expression of T cell activation and differentiation markers. No significant differences were detected between women with or without endometrial CT infection. Participants who remained follow-up negative (FU-) showed higher frequencies of CD4 T central memory (TCM) Th1, Th17, Th1/17, and Th17 DN but reduced CD4 TEM Th2 cells than FU+ participants. Expression of markers associated with central memory and Th17 lineage were increased on T cell subsets among FU- participants. These data indicate that peripheral T cells exhibit distinct features associated with resistance to CT reinfection. The highly plastic Th17 lineage appears to contribute to protection. Addressing these immune nuances could promote efficacy of CT vaccines. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/551709v2_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1df97e7org.highwire.dtl.DTLVardef@6deabcorg.highwire.dtl.DTLVardef@4e02d0org.highwire.dtl.DTLVardef@19ae25d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗