Browsing by Subject "Chlamydia Infections"
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Item Azithromycin efficacy in asymptomatic rectal chlamydial infection in MSM: A more definitive answer soon?(Wolters Kluwer, 2017-07) Batteiger, Byron E.; Medicine, School of MedicineItem Chlamydia muridarum infection of macrophages elicits bactericidal nitric oxide production via reactive oxygen species and cathepsin B(IAI, 2015-08) Rajaram, Krithika; Nelson, David E.; Department of Microbiology and Immunology, IU School of MedicineThe ability of certain species of Chlamydia to inhibit the biogenesis of phagolysosomes permits their survival and replication within macrophages. The survival of macrophage-adapted chlamydiae correlates with the multiplicity of infection (MOI), and optimal chlamydial growth occurs in macrophages infected at an MOI of ≤1. In this study, we examined the replicative capacity of Chlamydia muridarum in the RAW 264.7 murine macrophage cell line at different MOIs. C. muridarum productively infected these macrophages at low MOIs but yielded few viable elementary bodies (EBs) when macrophages were infected at a moderate (10) or high (100) MOI. While high MOIs caused cytotoxicity and irreversible host cell death, macrophages infected at a moderate MOI did not show signs of cytotoxicity until late in the infectious cycle. Inhibition of host protein synthesis rescued C. muridarum in macrophages infected at a moderate MOI, implying that chlamydial growth was blocked by activated defense mechanisms. Conditioned medium from these macrophages was antichlamydial and contained elevated levels of interleukin 1β (IL-1β), IL-6, IL-10, and beta interferon (IFN-β). Macrophage activation depended on Toll-like receptor 2 (TLR2) signaling, and cytokine production required live, transcriptionally active chlamydiae. A hydroxyl radical scavenger and inhibitors of inducible nitric oxide synthase (iNOS) and cathepsin B also reversed chlamydial killing. High levels of reactive oxygen species (ROS) led to an increase in cathepsin B activity, and pharmacological inhibition of ROS and cathepsin B reduced iNOS expression. Our data demonstrate that MOI-dependent TLR2 activation of macrophages results in iNOS induction via a novel ROS- and cathepsin-dependent mechanism to facilitate C. muridarum clearance.Item Longitudinal associations among relationship factors, partner change, and sexually transmitted infection acquisition in adolescent women(Lippincott, Williams & Wilkins, 2011-03) Ott, Mary A.; Katschke, Adrian; Tu, Wanzhu; Fortenberry, J. Dennis; Pediatrics, School of MedicineOBJECTIVES: New sex partners put adolescents at increased risk for sexually transmitted infections (STIs), even when these sex partners are nonoverlapping. Although the risk of partner change is well described, little is known about its antecedents. We prospectively examined associations between relationship characteristics, partner change, and subsequent STI during intervals of "serial monogamy." METHODS: As part of a longitudinal study, 332 adolescent women were interviewed and tested for gonorrhea, chlamydia, and trichomonas every 3 months for up to just over 6 years. Interviews covered partner-specific relationship characteristics and sexual behaviors. The quarterly interval, a 3-month period bracketed by interviews and STI testing, was the unit of analysis. We examined associations among relationship factors, partner change, and subsequent STI using a series of mixed regression models, controlling for age, STI at Time 1, and condom nonuse. RESULTS: Age, lower relationship quality, and lower levels of partner closeness to friends and family predicted partner change from Time 1 to Time 2. In turn, partner change was associated with acquisition of a new STI at Time 2. Although relationship factors did not exert a direct effect on STI at Time 2, they improved partner change-STI model fit. Similar patterns were seen with each organism. CONCLUSION: Relationship factors drive partner change, which in turn contributes to STI acquisition. STI prevention research may need to focus on the relationship antecedents to partner change, in addition to the partner change itself.Item Optimizing strategies for population-based chlamydia infection screening among young women: an age-structured system dynamics approach(Springer (Biomed Central Ltd.), 2015) Teng, Yu; Kong, Nan; Tu, Wanzhu; Department of Biostatistics, School of Public HealthBACKGROUND: Chlamydia infection (CT) is one of the most commonly reported sexually transmitted diseases. It is often referred to as a "silent" disease with the majority of infected people having no symptoms. Without early detection, it can progress to serious reproductive and other health problems. Economical identification of asymptomatically infected is a key public health challenge. Increasing evidence suggests that CT infection risk varies over the range of adolescence. Hence, age-dependent screening strategies with more frequent testing for certain age groups of higher risk may be cost-saving in controlling the disease. METHODS: We study the optimization of age-dependent screening strategies for population-based chlamydia infection screening among young women. We develop an age-structured compartment model for CT natural progress, screening, and treatment. We apply parameter optimization on the resultant PDE-based system dynamical models with the objective of minimizing the total care spending, including screening and treatment costs during the program period and anticipated costs of treating the sequelae afterwards). For ease of practical implementation, we also search for the best screening initiation age for strategies with a constant screening frequency. RESULTS: The optimal age-dependent strategies identified outperform the current CDC recommendations both in terms of total care spending and disease prevalence at the termination of the program. For example, the age-dependent strategy that allows monthly screening rate changes can save about 5% of the total spending. Our results suggest early initiation of CT screening is likely beneficial to the cost saving and prevalence reduction. Finally, our results imply that the strategy design may not be sensitive to accurate quantification of the age-specific CT infection risk if screening initiation age and screening rate are the only decisions to make. CONCLUSIONS: Our research demonstrates the potential economic benefit of age-dependent screening strategy design for population-based screening programs. It also showcases the applicability of age-structured system dynamical modeling to infectious disease control with increasing evidence on the age differences in infection risk. The research can be further improved with consideration of the difference between first-time infection and reinfection, as well as population heterogeneity in sexual partnership.Item Proceed With Caution in Generating Evidence in the “Oropharyngeal-Anorectal Chlamydia Hypothesis” in Humans(Wolters Kluwer, 2019-09-01) Leenen, Jeanine; van Liere, Geneviève A. F. S.; Hoebe, Christian J. P. A.; Dukers-Muijrers, Nicole H. T. M.; Microbiology and Immunology, School of MedicineItem Reply to, “Proceed With Caution in Generating Evidence in the ‘Oropharyngeal-Anorectal Chlamydia Hypothesis’ in Humans”(Wolters Kluwer, 2019-09-01) Batteiger, Teresa A.; Jordan, Stephen J.; Toh, Evelyn; Nelson, David E.; Microbiology and Immunology, School of MedicineItem Role of STAT1 in Chlamydia-Induced Type-1 Interferon Production in Oviduct Epithelial Cells(Mary Ann Liebert, 2015-11) Hosey, Kristen Lynette; Hu, Sishun; Derbigny, Wilbert Alfred; Department of Microbiology & Immunology, IU School of MedicineWe previously reported that Chlamydia muridarum-infected murine oviduct epithelial cells (OE cells) secrete interferon β (IFN-β) in a mostly TLR3-dependent manner. However, C. muridarum-infected TLR3-deficient OE cells were still able to secrete detectable levels of IFN-β into the supernatants, suggesting that other signaling pathways contribute to Chlamydia-induced IFN-β synthesis in these cells. We investigated the role of STAT1 as a possible contributor in the Chlamydia-induced type-1 IFN production in wild-type (WT) and TLR3-deficient OE cells to ascertain its putative role at early- and late-times during Chlamydia infection. Our data show that C. muridarum infection significantly increased STAT1 gene expression and protein activation in WT OE cells; however, TLR3-deficient OE cells showed diminished STAT1 protein activation and gene expression. There was significantly less IFN-β detected in the supernatants of C. muridarum-infected OE cells derived from mice deficient in STAT1 when compared with WT OE cells, which suggest that STAT1 is required for the optimal synthesis of IFN-β during infection. Real-time quantitative polymerase chain reaction analyses of signaling components of the type-1 IFN signaling pathway demonstrated equal upregulation in the expression of STAT2 and IRF7 genes in the WT and TLR3-deficient OE cells, but no upregulation in these genes in the STAT1-deficient OE cells. Finally, experiments in which INFAR1 was blocked with neutralizing antibody revealed that IFNAR1-mediated signaling was critical to the Chlamydia-induced upregulation in IFN-α gene transcription, but had no role in the Chlamydia-induced upregulation in IFN-β gene transcription.Item Toll-like receptor 3 (TLR3) promotes the resolution of Chlamydia muridarum genital tract infection in congenic C57BL/6N mice(Public Library of Science, 2018-04-06) Carrasco, Sebastian E.; Hu, Sishun; Imai, Denise M.; Kumar, Ramesh; Sandusky, George E.; Yang, X. Frank; Derbigny, Wilbert A.; Microbiology and Immunology, School of MedicineChlamydia trachomatis urogenital serovars primarily replicate in epithelial cells lining the reproductive tract. Epithelial cells recognize Chlamydia through cell surface and cytosolic receptors, and/or endosomal innate receptors such as Toll-like receptors (TLRs). Activation of these receptors triggers both innate and adaptive immune mechanisms that are required for chlamydial clearance, but are also responsible for the immunopathology in the reproductive tract. We previously demonstrated that Chlamydia muridarum (Cm) induces IFN-β in oviduct epithelial cells (OE) in a TLR3-dependent manner, and that the synthesis of several cytokines and chemokines are diminished in Cm-challenged OE derived from TLR3-/- 129S1 mice. Furthermore, our in vitro studies showed that Cm replication in TLR3-/- OE is more efficient than in wild-type OE. Because TLR3 modulates the release inflammatory mediators involved in host defense during Cm infection, we hypothesized that TLR3 plays a protective role against Cm-induced genital tract pathology in congenic C57BL/6N mice. Using the Cm mouse model for human Chlamydia genital tract infections, we demonstrated that TLR3-/- mice had increased Cm shedding during early and mid-stage genital infection. In early stage infection, TLR3-/- mice showed a diminished synthesis of IFN-β, IL-1β, and IL-6, but enhanced production of IL-10, TNF-α, and IFN-γ. In mid-stage infection, TLR3-/- mice exhibited significantly enhanced lymphocytic endometritis and salpingitis than wild-type mice. These lymphocytes were predominantly scattered along the endometrial stroma and the associated smooth muscle, and the lamina propria supporting the oviducts. Surprisingly, our data show that CD4+ T-cells are significantly enhanced in the genital tract TLR3-/- mice during mid-stage Chlamydial infection. In late-stage infections, both mouse strains developed hydrosalpinx; however, the extent of hydrosalpinx was more severe in TLR3-/- mice. Together, these data suggest that TLR3 promotes the clearance of Cm during early and mid-stages of genital tract infection, and that loss of TLR3 is detrimental in the development hydrosalpinx.