Transcervical Mouse Infections with Chlamydia trachomatis and  Determination of Bacterial Burden

Rajeeve, Karthika; Sivadasan, Rajeeve

doi:10.21769/bioprotoc.3506

Cited by 6 publications

(7 citation statements)

References 16 publications

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“… 64 , 68 To address these limitations, an intracervical murine infection model has been developed in which C. trachomatis infection in mice upper genital tract can be established. 62 , 69 We aim to use this model to evaluate the efficacy of the OMV vaccine formulations, both individually and in combination, including the exploration of a single, bivalent formulation incorporating both C. trachomatis antigens coupled to the same OMV. 70 …”

Section: Discussionmentioning

confidence: 99%

Intranasal delivery of Salmonella OMVs decorated with Chlamydia trachomatis antigens induces specific local and systemic immune responses

Huynh,

Nolfi,

Medfai

et al. 2024

Human Vaccines & Immunotherapeutics

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Chlamydia trachomatis is an obligate intracellular pathogen responsible for the most prevalent bacterial sexually transmitted disease globally. The high prevalence of chlamydial infections underscores the urgent need for licensed and effective vaccines to prevent transmission in populations. Bacterial outer membrane vesicles (OMVs) have emerged as promising mucosal vaccine carriers due to their inherent adjuvant properties and the ability to display heterologous antigens. In this proof-of-concept study, we evaluated the immunogenicity of Salmonella OMVs decorated with C. trachomatis MOMP-derived CTH522 or HtrA antigens in mice. Following a prime-boost intranasal vaccination approach, two OMV-based C. trachomatis vaccines elicited significant humoral responses specific to the antigens in both systemic and vaginal compartments. Furthermore, we demonstrated strong antigen-specific IFN-γ and IL17a responses in splenocytes and cervical lymph node cells of vaccinated mice, indicating CD4 + Th1 and Th17 biased immune responses. Notably, the OMV-CTH522 vaccine also induced the production of spleen-derived CD8 + T cells expressing IFN-γ. In conclusion, these results highlight the potential of OMV-based C. trachomatis vaccines for successful use in future challenge studies and demonstrate the suitability of our modular OMV platform for intranasal vaccine applications.

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Section: Discussionmentioning

confidence: 99%

Intranasal delivery of Salmonella OMVs decorated with Chlamydia trachomatis antigens induces specific local and systemic immune responses

Huynh,

Nolfi,

Medfai

et al. 2024

Human Vaccines & Immunotherapeutics

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“…A likely explanation for this discrepancy is the repeated observation that murine intravaginal infections with C. trachomatis fail to ascend into the upper genital tract and are readily cleared by the innate immune system ( 82 , 83 ). That being said, recent work has demonstrated transcervical infections with C. trachomatis serovar D severely impact fertility in the mouse model ( 84 , 85 ), emphasizing the importance of infection of cervical epithelial cells to the development of chlamydial sequelae. Intriguingly, the immune response to transcervical C. trachomatis infections includes robust recruitment of CD4+ T-cells and secretion of IL-17 ( 85 , 86 )—features consistent with the cell type-intrinsic induction of IL-17 expression and CD4+ T-cell survival and chemotactic factors (e.g., IL-6 and IL-8) we observe in both uninfected and infected HCECs.…”

Section: Discussionmentioning

confidence: 99%

Chlamydial YAP activation in host endocervical epithelial cells mediates pro-fibrotic paracrine stimulation of fibroblasts

Caven,

Carabeo

2023

mSystems

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Infection of the female genital tract by Chlamydia trachomatis can produce severe fibrotic sequelae, including tubal factor infertility and ectopic pregnancy. While infection demonstrably mediates a pro-fibrotic response in host cells, it remains unclear if intrinsic properties of the upper genital tract exacerbate chlamydial fibrosis. The relatively sterile environment of the upper genital tract is primed for a pro-inflammatory response to infection, potentially enhancing fibrosis; however, subclinical C. trachomatis infections still develop fibrosis-related sequelae. Here, we compare infection-associated and steady-state gene expression of primary human cervical and vaginal epithelial cells. In the former, we observe enhanced baseline expression and infection-mediated induction of fibrosis-associated signal factors (e.g., TGFA , IL6 , IL8 , and IL20 ), implying predisposition to Chlamydia -associated pro-fibrotic signaling. Transcription factor enrichment analysis identified regulatory targets of YAP, a transcriptional cofactor induced by infection of cervical epithelial cells, but not vaginal epithelial cells. YAP target genes induced by infection include secreted fibroblast-activating signal factors; therefore, we developed an in vitro model involving coculture of infected endocervical epithelial cells with uninfected fibroblasts. Coculture enhanced fibroblast expression of type I collagen, as well as prompting reproducible (albeit statistically insignificant) induction of α-smooth muscle actin. Fibroblast collagen induction was sensitive to siRNA-mediated YAP knockdown in infected epithelial cells, implicating chlamydial YAP activation in this effect. Collectively, our results present a novel mechanism of fibrosis initiated by Chlamydia , wherein infection-mediated induction of host YAP facilitates pro-fibrotic intercellular communication. Chlamydial YAP activation in cervical epithelial cells is thus a determinant of this tissue’s susceptibility to fibrosis. IMPORTANCE Chronic or repeated infection of the female upper genital tract by C. trachomatis can lead to severe fibrotic sequelae, including tubal factor infertility and ectopic pregnancy. However, the molecular mechanisms underlying this effect are unclear. In this report, we define a transcriptional program specific to C. trachomatis infection of the upper genital tract, identifying tissue-specific induction of host YAP—a pro-fibrotic transcriptional cofactor—as a potential driver of infection-mediated fibrotic gene expression. Furthermore, we show that infected endocervical epithelial cells stimulate collagen production by fibroblasts and implicate chlamydial induction of YAP in this effect. Our results define a mechanism by which infection mediates tissue-level fibrotic pathology via paracrine signaling and identify YAP as a potential therapeutic target for the prevention of Chlamydia -associated scarring of the female genital tract.

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“…However, the intensity of infection induced by C. muridarum is acute whereas that of C. trachomatis is known to be chronic, and the IFNγ mediated bacterial clearance mechanisms of both these species also differ, thereby making the comparison inaccurate [41,42]. When C. trachomatis is used for inducing vaginal infection in a mouse model, it does not lead to ascending genital tract infection and fallopian tube pathology as seen in humans, making the model imperfect [43]. Recently, a trans cervical method of infection was adopted to facilitate development of an ascending infection in uterus and fallopian tubes, allowing duplication of human infection conditions [38,43].…”

Section: Preclinical Evaluation Of Vaccine Candidatesmentioning

confidence: 99%

“…When C. trachomatis is used for inducing vaginal infection in a mouse model, it does not lead to ascending genital tract infection and fallopian tube pathology as seen in humans, making the model imperfect [43]. Recently, a trans cervical method of infection was adopted to facilitate development of an ascending infection in uterus and fallopian tubes, allowing duplication of human infection conditions [38,43]. C. trachomatis and C. suis have been found to induce homo-and heterologous IFNγ + TNFα + CD4 T cell based immune responses in pigs, indicating possibility of cross-protection between them and humans [44].…”

Section: Preclinical Evaluation Of Vaccine Candidatesmentioning

confidence: 99%

Chlamydia trachomatis: quest for an eye-opening vaccine breakthrough

Chavda

Pandya

Kypreos

et al. 2022

Expert Review of Vaccines

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Introduction:Chlamydia trachomatis, commonly referred to as chlamydia (a bacterium), is a common sexually transmitted infection, and if attended to early, it can be treatable. However, if left untreated it can lead to serious consequences. C. trachomatis infects both females and males although its occurrence in females is more common, and it can spread to the eyes causing disease and in some case blindness. Area covered: With ongoing attempts in the most impoverished regions of the country, trachoma will be eradicated as a blinding disease by the year 2022. A prophylactic vaccine candidate with established safety and efficacy is a cogent tool to achieve this goal. This manuscript covers the vaccine development programs for chlamydial infection. Expert opinion: Currently, the Surgery Antibiotics Facial Environmental (SAFE) program is being implemented in endemic countries in order to reduce transmission and control of the disease. Vaccines have been shown over the years to protect against infectious diseases. Charge variantbased adjuvant can also be used for the successful delivery of chlamydial specific antigen for efficient vaccine delivery through nano delivery platform. Thus, a vaccine against C. trachomatis would be of great public health benefit.

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Transcervical Mouse Infections with Chlamydia trachomatis and Determination of Bacterial Burden

Abstract: Bio-protocol 10(03): e3506.

Cited by 6 publications

References 16 publications

Intranasal delivery of Salmonella OMVs decorated with Chlamydia trachomatis antigens induces specific local and systemic immune responses

Intranasal delivery of Salmonella OMVs decorated with Chlamydia trachomatis antigens induces specific local and systemic immune responses

Chlamydial YAP activation in host endocervical epithelial cells mediates pro-fibrotic paracrine stimulation of fibroblasts

Chlamydia trachomatis: quest for an eye-opening vaccine breakthrough

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