Cervical Cytokines Associated With Chlamydia trachomatis Susceptibility and Protection

Poston, Taylor B.; Lee, De’Ashia E.; Darville, Toni; Zhong, Wujuan; Li, Dong; O’Connell, Catherine M.; Wiesenfeld, Harold C.; Hillier, Sharon L.; Sempowski, Gregory D.; Zheng, Xiaojing

doi:10.1093/infdis/jiz087

Cited by 39 publications

(34 citation statements)

References 51 publications

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“…CXCL10, CXCL11 and RANTES are chemoattractants for multiple immune cell types, including T cells (52)(53)(54)(55). We have previously detected these proteins in cervical secretions from C. trachomatis-infected women (6) and CXCL10 mRNA in endometrial biopsy specimens of women with endometrial infection (56). Multiple studies have established that an adaptive CD4 Th1 T-cell response is essential to combat chlamydial infection (57)(58)(59)(60)(61)(62).…”

Section: Muc5b Muc4 Muc16 and Muc1 (See Tablementioning

confidence: 99%

Human Fallopian Tube Epithelial Cell Culture Model To Study Host Responses to Chlamydia trachomatis Infection

et al. 2020

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Chlamydia trachomatis infection of the human Fallopian tubes can lead to damaging inflammation and scarring, ultimately resulting in infertility. To study the human cellular responses to chlamydial infection, researchers have frequently used transformed cell lines that can have limited translational relevance. We developed a primary human Fallopian tube epithelial cell model based on a method previously established for culture of primary human bronchial epithelial cells. After protease digestion and physical dissociation of excised Fallopian tubes, epithelial cell precursors were expanded in growth factor-containing medium. Expanded cells were cryopreserved to generate a biobank of cells from multiple donors and cultured at an air-liquid interface. Culture conditions stimulated cellular differentiation into polarized mucin-secreting and multi-ciliated cells, recapitulating the architecture of human Fallopian tube epithelium. The polarized and differentiated cells were infected with a clinical isolate of C. trachomatis, and inclusions containing chlamydial developmental forms were visualized by fluorescence and electron microscopy. Apical secretions from infected cells contained increased amounts of proteins associated with chlamydial growth and replication, including transferrin receptor protein 1, the amino acid transporters SLC3A2 and SLC1A5, and the T cell chemoattractants CXCL10, CXCL11, and RANTES. Flow cytometry revealed that chlamydial infection induced cell surface expression of T cell homing and activation proteins including ICAM-1, VCAM-1, HLA class I and II, and IFNγR. This human Fallopian tube epithelial cell culture model is an important tool with translational potential for studying cellular responses to Chlamydia and other sexually-transmitted pathogens.

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Section: Muc5b Muc4 Muc16 and Muc1 (See Tablementioning

confidence: 99%

Human Fallopian Tube Epithelial Cell Culture Model To Study Host Responses to Chlamydia trachomatis Infection

et al. 2020

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“…Moreover, CXCL10 and related chemokines have recently been found to promote immune-mediated pathology during C. trachomatis infection in mice 29 . Similarly, a recent study of women with C. trachomatis infection found elevated levels of CXCL10 in cervical secretions to be associated with endometrial chlamydial infection 23 .…”

Section: Discussionmentioning

confidence: 87%

“…Infection can remain asymptomatic, present as acute infection, or lead to pelvic inflammatory disease (PID) and infertility [19][20][21] . CXCL10 is produced after C. trachomatis infection in humans 22,23 and mice [24][25][26] and regulates the recruitment of CD4 + and CD8 + T-cells through the CXCR3 chemokine receptor. Because CXCR3 + cells can promote C. trachomatis clearance 27,28 and immune-mediated pathology 29 , CXCL10 is a critical determinant of C. trachomatis disease.…”

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confidence: 99%

Modeling of variables in cellular infection reveals CXCL10 levels are regulated by human genetic variation and the Chlamydia-encoded CPAF protease

Schott

Antonia

Wang

et al. 2020

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Susceptibility to infectious diseases is determined by a complex interaction between host and pathogen. For infections with the obligate intracellular bacterium Chlamydia trachomatis, variation in immune activation and disease presentation are regulated by both host genetic diversity and pathogen immune evasion. Previously, we discovered a single nucleotide polymorphism (rs2869462) associated with absolute abundance of CXCL10, a pro-inflammatory T-cell chemokine. Here, we report that levels of CXCL10 change during C. trachomatis infection of cultured cells in a manner dependent on both host and pathogen. Linear modeling of cellular traits associated with CXCL10 levels identified a strong, negative correlation with bacterial burden, suggesting that C. trachomatis actively suppresses CXCL10. We identified the pathogen-encoded factor responsible for this suppression as the chlamydial protease- or proteasome-like activity factor, CPAF. Further, we applied our modeling approach to other host cytokines in response to C. trachomatis and found evidence that RANTES, another T-cell chemoattractant, is actively suppressed by Chlamydia. However, this observed suppression of RANTES is not mediated by CPAF. Overall, our results demonstrate that CPAF suppresses CXCL10 to evade the host cytokine response and that modeling of cellular infection parameters can reveal previously unrecognized facets of host–pathogen interactions.

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“…High c-hsp60 antibody titres in koalas have been associated with fibrous occlusion of the uterus or uterine tube, however their role in chlamydial pathogenesis in koalas remains unclear as they were also associated with lower levels of active inflammation and fewer chlamydial inclusions 28 . Human studies suggest that although the Class II MHC defined anti-chlamydial antibody response appears to be important for chlamydial clearance and c-hsp60 antibodies are protective, it does not always prevent pathology 29,30 .…”

Section: Discussionmentioning

confidence: 99%

Koala immunogenetics and chlamydial strain type are more directly involved in chlamydial disease progression in koalas from two south east Queensland koala populations than koala retrovirus subtypes

Robbins

Hanger

Jelocnik

et al. 2020

Sci Rep

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Chlamydial disease control is increasingly utilised as a management tool to stabilise declining koala populations, and yet we have a limited understanding of the factors that contribute to disease progression. To examine the impact of host and pathogen genetics, we selected two geographically separated south east Queensland koala populations, differentially affected by chlamydial disease, and analysed koala major histocompatibility complex (MHC) genes, circulating strains of Chlamydia pecorum and koala retrovirus (KoRV) subtypes in longitudinally sampled, well-defined clinical groups. We found that koala immunogenetics and chlamydial genotypes differed between the populations. Disease progression was associated with specific MHC alleles, and we identified two putative susceptibility (DCb 03, DBb 04) and protective (DAb 10, UC 01:01) variants. Chlamydial genotypes belonging to both Multi-Locus Sequence Typing sequence type (ST) 69 and ompA genotype F were associated with disease progression, whereas ST 281 was associated with the absence of disease. We also detected different ompA genotypes, but not different STs, when long-term infections were monitored over time. By comparison, KoRV profiles were not significantly associated with disease progression. These findings suggest that chlamydial genotypes vary in pathogenicity and that koala immunogenetics and chlamydial strains are more directly involved in disease progression than KoRV subtypes.

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Cervical Cytokines Associated With Chlamydia trachomatis Susceptibility and Protection

Cited by 39 publications

References 51 publications

Human Fallopian Tube Epithelial Cell Culture Model To Study Host Responses to Chlamydia trachomatis Infection

Human Fallopian Tube Epithelial Cell Culture Model To Study Host Responses to Chlamydia trachomatis Infection

Modeling of variables in cellular infection reveals CXCL10 levels are regulated by human genetic variation and the Chlamydia-encoded CPAF protease

Koala immunogenetics and chlamydial strain type are more directly involved in chlamydial disease progression in koalas from two south east Queensland koala populations than koala retrovirus subtypes

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