<i>Chlamydia muridarum</i> Infection Associated Host Micro<scp>RNA</scp>s in the Murine Genital Tract and Contribution to Generation of Host Immune Response

Gupta, Rishein; Arkatkar, Tanvi; Yu, Jieh Juen; Wali, Shradha; Haskins, William E.; Chambers, James P.; Murthy, Ashlesh K.; Bakar, Sazaly Abu; Guentzel, M. Neal; Arulanandam, Bernard P.

doi:10.1111/aji.12281

Cited by 25 publications

(59 citation statements)

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“…Transcriptome-wide or sequencing approaches have revealed the role for specific immune genes and associated pathways following infection with Ct-plasmid-sufficient and -deficient strains (Porcella et al 2015; Carlson et al 2008; Ferreira et al 2013; Qu et al 2015). Similarly, regulatory genetic species, namely microRNAs of bacterial and host origin have revealed the role(s) in growth and cellular function following infection (Derrick et al 2013; Furuse et al 2014; Gupta et al 2015; Yeruva et al 2014; Igietseme et al 2013). Proteomic studies have identified immunodominant, T- and B cell chlamydial antigens involved in primary infection and vaccination (Cruz-Fisher et al 2011; Wang et al 2010; Karunakaran et al 2015; Picard et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Guinea pig genital tract lipidome reveals in vivo and in vitro regulation of phosphatidylcholine 16:0/18:1 and contribution to Chlamydia trachomatis serovar D infectivity

Wali

Gupta

et al. 2016

Metabolomics

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Introduction Chlamydia trachomatis (Ct), is the leading cause of sexually transmitted infections worldwide. Host transcriptomic- or proteomic profiling studies have identified key molecules involved in establishment of Ct infection or the generation of anti Ct-immunity. However, the contribution of the host metabolome is not known. Objectives The objective of this study was to determine the contribution of host metabolites in genital Ct infection. Methods We used high-performance liquid chromatography-mass spectrometry, and mapped lipid profiles in genital swabs obtained from female guinea pigs at days 3, 9, 15, 30 and 65 post Ct serovar D intravaginal infection. Results Across all time points assessed, 13 distinct lipid species including choline, ethanolamine and glycerol were detected. Amongst these metabolites, phosphatidylcholine (PC) was the predominant phospholipid detected from animals actively shedding bacteria i.e., at 3, 9, and 15 days post infection. However, at days 30 and 65 when the animals had cleared the infection, PC was observed to be decreased compared to previous time points. Mass spectrometry analyses of PC produced in guinea pigs (in vivo) and 104C1 guinea pig cell line (in vitro) revealed distinct PC species following Ct D infection. Amongst these, PC 16:0/18:1 was significantly upregulated following Ct D infection (p < 0.05, >twofold change) in vivo and in vitro infection models investigated in this report. Exogenous addition of PC 16:0/18:1 resulted in significant increase in Ct D in Hela 229 cells. Conclusion This study demonstrates a role for host metabolite, PC 16:0/18:1 in regulating genital Ct infection in vivo and in vitro.

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Section: Introductionmentioning

confidence: 99%

Guinea pig genital tract lipidome reveals in vivo and in vitro regulation of phosphatidylcholine 16:0/18:1 and contribution to Chlamydia trachomatis serovar D infectivity

Wali

Gupta

et al. 2016

Metabolomics

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“…Nigg V infection results in a higher bacterial load; thus, it is possible that increased inflammatory responses and miRNA expression are due to a higher replicative capacity of the chlamydiae. Interestingly, Gupta et al (45) showed no overall differences in miRNA expression with three different doses (5 ϫ 10 4 , 5 ϫ 10 5 , and 5 ϫ 10 6 ), suggesting that Nigg V interaction with host cells is different from that of Nigg A in terms of regulating host miRNA expression and is not necessarily related to numbers of microorganisms. Regardless of the replicative capacity of bacteria, our results suggest that miRNAs expression regulates the inflammatory response, thus dictating the pathological outcome.…”

Section: Discussionmentioning

confidence: 97%

“…The results showed that miRNAs were differentially expressed and cytokine responses were significantly upregulated in Nigg V -infected mice, correlating with oviduct pathology. A study by Gupta et al (45) showed significant downregulation of miR-125b-5p, miR-16, miR-214, miR-23b, miR-135a, miR-182, miR-183, miR-30c, and miR-30e on day 6 following genital infection of mice. More recently, it has been demonstrated that during ocular C. trachomatis infection, upregulation of miR-155 and downregulation of miR-184 correlated with conjunctival inflammation (43).…”

Section: Discussionmentioning

confidence: 97%

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MicroRNAs Modulate Pathogenesis Resulting from Chlamydial Infection in Mice

et al. 2017

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Not all women infected with chlamydiae develop upper genital tract disease, but the reason(s) for this remains undefined. Host genetics and hormonal changes associated with the menstrual cycle are possible explanations for variable infection outcomes. It is also possible that disease severity depends on the virulence of the chlamydial inoculum. It is likely that the inoculum contains multiple genetic variants, differing in virulence. If the virulent variants dominate, then the individual is more likely to develop severe disease. Based on our previous studies, we hypothesized that the relative degree of virulence of a chlamydial population dictates the microRNA (miRNA) expression profile of the host, which, in turn, through regulation of the host inflammatory response, determines disease severity. Thus, we infected C57BL/6 mice with two populations of Chlamydia muridarum, each comprised of multiple genetic variants and differing in virulence: an attenuated strain (Nigg A ) and a virulent strain (Nigg V ). Nigg A and Nigg V elicited upper tract pathology in 54% and 91% of mice, respectively. miRNA expression analysis in Nigg V -infected mice showed significant downregulation of miRNAs involved in dampening fibrosis (miR-200b, miR-200b-5p, and 200b-3p miR-200a-3p) and in transcriptional regulation of cytokine responses (miR-148a-3p, miR-152-3p, miR-132, and miR-212) and upregulation of profibrotic miRNAs (miR-142, and miR-147). Downregulated miRNAs were associated with increased expression of interleukin 8 (IL-8), CXCL2, IL-1␤, tumor necrosis factor alpha (TNF-␣), and IL-6. Infection with Nigg V but not Nigg A led to decreased expression of Dicer and Ago 2, suggesting that Nigg V interaction with host cells inhibits expression of the miRNA biogenesis machinery, leading to increased cytokine expression and pathology.

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“…Recently, we reported alteration of host microRNA (miR) profiles during the early stage (day 6) of C. muridarum infection . These short, non‐coding RNA species modulate gene function post‐transcriptionally by direct binding to target gene mRNA, influencing biological processes including immune function and reproduction, and constitute potential biomarkers for genital C. trachomatis infection in humans .…”

Section: Introductionmentioning

confidence: 99%

Murine MicroRNA‐214 regulates intracellular adhesion molecule (ICAM1) gene expression in genital Chlamydia muridarum infection

Arkatkar

Gupta

et al. 2015

Immunology

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SummaryThe hallmark of chlamydial infection is the development of upper genital pathology in the form of hydrosalpinx and oviduct and/or tubal dilatation. Although molecular events leading to genital tissue presentation and cellular architectural remodelling are unclear, early-stage host immune responses are believed to contribute to these long-term sequelae. Recently, we reported the contribution of selected infection-associated microRNAs (miRs) in the generation of host immunity at early-stage infection (day 6 after intravaginal Chlamydia muridarum challenge in C57BL/6 mice). In this report, we describe the contribution of an infection-associated micro-RNA, i.e. miR-214, to host immunity. Chlamydia muridarum infection in the C57BL/6 mouse genital tract significantly down-regulated miR-214 while up-regulating intracellular adhesion molecule 1 (ICAM1) gene expression. These in vivo observations were confirmed by establishing direct regulation of ICAM-1 by miR-214 in ex vivo genital cell cultures in the presence of miR-214 mimic and inhibitor. Because, ICAM-1 contributes to recruitment of neutrophils following infection, we also demonstrated that alteration of ICAM1 by miR-214 in interleukin-17A-deficient (IL-17A À/À ) mice correlated with reduction of neutrophils infiltrating genital tissue at day 6 after challenge. Additionally, these early-stage events resulted in significantly decreased genital pathology in IL-17A À/À mice compared with C57BL/6 mice. This report provides evidence for earlystage regulation of ICAM1 by microRNAs, resulting in reduction of genital pathology associated with chlamydial infection.

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Chlamydia muridarum Infection Associated Host MicroRNAs in the Murine Genital Tract and Contribution to Generation of Host Immune Response

Cited by 25 publications

References 85 publications

Guinea pig genital tract lipidome reveals in vivo and in vitro regulation of phosphatidylcholine 16:0/18:1 and contribution to Chlamydia trachomatis serovar D infectivity

Guinea pig genital tract lipidome reveals in vivo and in vitro regulation of phosphatidylcholine 16:0/18:1 and contribution to Chlamydia trachomatis serovar D infectivity

MicroRNAs Modulate Pathogenesis Resulting from Chlamydial Infection in Mice

Murine MicroRNA‐214 regulates intracellular adhesion molecule (ICAM1) gene expression in genital Chlamydia muridarum infection

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