Lower Levels of Cervicovaginal Tryptophan Are Associated With Natural Clearance of Chlamydia in Women

Jordan, Stephen J.; Olson, Kristin; Barnes, Stephen R.; Wilson, Landon; Berryhill, Taylor F.; Bakshi, Rakesh K.; Brown, Laura L.; Press, Christen G.; Geisler, William M.

doi:10.1093/infdis/jix240

Cited by 16 publications

(14 citation statements)

References 16 publications

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“…Advancements in both targeted and comprehensive untargeted metabolomics have already provided evidence for divergent metabolic activity associated with vaginal dysbiotic states, including abnormalities in sugar compound, short chain fatty acid, lipid, biogenic amine and amino acid metabolism . However, little is known about vaginal metabolic profile disturbances in the context of STIs or metabolite biomarkers that may be associated with infection risk . Studies assessing vaginal metabolic profiles in the context of BV treatment (such as rifaximin) efficacy, can inform the development of effective clinical treatments .…”

Section: Introductionmentioning

confidence: 99%

The genital tract and rectal microbiomes: their role in HIV susceptibility and prevention in women

et al. 2019

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Introduction Young women in sub‐Saharan Africa are disproportionately affected by HIV, accounting for 25% of all new infections in 2017. Several behavioural and biological factors are known to impact a young woman's vulnerability for acquiring HIV. One key, but lesser understood, biological factor impacting vulnerability is the vaginal microbiome. This review describes the vaginal microbiome and examines its alterations, its influence on HIV acquisition as well as the efficacy of HIV prevention technologies, the role of the rectal microbiome in HIV acquisition, advances in technologies to study the microbiome and some future research directions. Discussion Although the composition of each woman's vaginal microbiome is unique, a microbiome dominated by Lactobacillus species is generally associated with a “healthy” vagina. Disturbances in the vaginal microbiota, characterized by a shift from a low‐diversity, Lactobacillus ‐dominant state to a high‐diversity non‐ Lactobacillus ‐dominant state, have been shown to be associated with a range of adverse reproductive health outcomes, including increasing the risk of genital inflammation and HIV acquisition. Gardnerella vaginalis and Prevotella bivia have been shown to contribute to both HIV risk and genital inflammation. In addition to impacting HIV risk, the composition of the vaginal microbiome affects the vaginal concentrations of some antiretroviral drugs, particularly those administered intravaginally, and thereby their efficacy as pre‐exposure prophylaxis (PrEP) for HIV prevention. Although the role of rectal microbiota in HIV acquisition in women is less well understood, the composition of this compartment's microbiome, particularly the presence of species of bacteria from the Prevotellaceae family likely contribute to HIV acquisition. Advances in technologies have facilitated the study of the genital microbiome's structure and function. While next‐generation sequencing advanced knowledge of the diversity and complexity of the vaginal microbiome, the emerging field of metaproteomics, which provides important information on vaginal bacterial community structure, diversity and function, is further shedding light on functionality of the vaginal microbiome and its relationship with bacterial vaginosis (BV), as well as antiretroviral PrEP efficacy. Conclusions A better understanding of the composition, structure and function of the microbiome is needed to identify opportunities to alter the vaginal microbiome and prevent BV and reduce the risk of HIV acquisition.

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Section: Introductionmentioning

confidence: 99%

The genital tract and rectal microbiomes: their role in HIV susceptibility and prevention in women

et al. 2019

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“…C. trachomatis aberrant bodies were also identified in infected women, and were associated with low IFN-γ levels in the genital tract [14]. Furthermore, low vaginal tryptophan levels were shown to be associated with spontaneous resolution of C. trachomatis infections in women [15]. Although chlamydial death due to tryptophan depletion via IFN-γ-induced IDO1 axis, has been well characterized in vitro, relatively few studies have measured IDO1 expression levels and its enzymatic activity in the actual infection site [16].…”

Section: Introductionmentioning

confidence: 99%

High expression of IDO1 and TGF-β1 during recurrence and post infection clearance with Chlamydia trachomatis, are independent of host IFN-γ response

2019

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Background Chlamydia trachomatis infections in women continue to be a major public health concern due to their high prevalence and consequent reproductive morbidities. While antibiotics are usually efficient to clear the Chlamydia , repeat infections are common and may contribute to pathological outcomes. Interferon-gamma (IFN-γ)-mediated immunity has been suggested to be protective against reinfection, and represent an important anti-chlamydial agent, primarily via the induction of indoleamine-2,3 dioxygenase 1 (IDO1) enzyme. IDO1 catalyzes the degradation of tryptophan, which can eliminate C. trachomatis infection in vitro. Here, we sought to measure IDO1 expression levels and related immune markers during different C. trachomatis infection statuses (repeated vs single infection vs post antibiotic treatment), in vitro and in vivo. Methods In this study, we measured the expression levels of IDO1 and immune regulatory markers, transforming growth factor β1 (TGF-β1) and forkhead box P3 (FoxP3), in vaginal swab samples of C. trachomatis -infected women, with either single or repeated infection. In addition, we used an in vitro co-culture model of endometrial carcinoma cell-line and peripheral blood mononuclear cells (PBMCs) to measure the same immune markers. Results We found that in women with repeated C. trachomatis infections vaginal IDO1 and TGF-β1 expression levels were significantly increased. Whereas, women who cleared their infection post antibiotic treatment, had increased levels of IDO1 and TGF-β1, as well as FoxP3. Similarly, using the in vitro model, we found significant upregulation of IDO1 and TGF-β1 levels in the co-culture infected with C. trachomatis . Furthermore, we found that in PBMCs infected with C. trachomatis there was a significant upregulation in IDO1 levels, which was independent of IFN-γ. In fact, C. trachomatis infection in PBMCs failed to induce IFN-γ levels in comparison to the uninfected culture. Conclusions Our data provide evidence for a regulatory immune response comprised of IDO1, TGF-β1 and FoxP3 in women post antibiotic treatment. In this study, we demonstrated a significant increase in IDO1 expression levels in response to C. trachomatis infection, both in vivo and in vitro, without elevated IFN-γ levels. This study implicates IDO1 and TGF-β1 as part of the immune response to repeated C. trachomatis infections, independently of IFN-γ. Electronic supplementary material The online version of this article (10.1186/s12879-019-3843-4) contains supplementary material, which is available to authorized users.

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“…Indole produced by dysbiotic genital microbiomes can be salvaged by C. trachomatis to evade tryptophan starvation imposed by IFN-γ (3,6,7). While indole-producing bacterial species can be isolated from vaginal samples (6), IFN-γ levels found at infection sites are likely insufficient by themselves to drive tryptophan starvation (6,63,79). Although a role for other cytokines in driving tryptophan starvation is likely, it should be noted that significant levels of cervicovaginal tryptophan continue to be detected in the majority of women who have spontaneously cleared their chlamydial infection (79).…”

Section: Discussionmentioning

confidence: 99%

“…While indole-producing bacterial species can be isolated from vaginal samples (6), IFN-γ levels found at infection sites are likely insufficient by themselves to drive tryptophan starvation (6,63,79). Although a role for other cytokines in driving tryptophan starvation is likely, it should be noted that significant levels of cervicovaginal tryptophan continue to be detected in the majority of women who have spontaneously cleared their chlamydial infection (79). Therefore, we suggest that clearance may result from a combination of multiple factors, including (i) a protective immune response that decreases tryptophan availability; and (ii) de-repression of trpRBA by indole derivatives.…”

Section: Discussionmentioning

confidence: 99%

Ammonia generation by tryptophan synthase drives a key genetic difference between genital and ocular Chlamydia trachomatis isolates

Sherchand

Aiyar

2019

Proc. Natl. Acad. Sci. U.S.A.

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A striking difference between genital and ocular clinical isolates of Chlamydia trachomatis is that only the former express a functional tryptophan synthase and therefore can synthesize tryptophan by indole salvage. Ocular isolates uniformly cannot use indole due to inactivating mutations within tryptophan synthase, indicating a selection against maintaining this enzyme in the ocular environment. Here, we demonstrate that this selection occurs in two steps. First, specific indole derivatives, produced by the human gut microbiome and present in serum, rapidly induce expression of C. trachomatis tryptophan synthase, even under conditions of tryptophan sufficiency. We demonstrate that these indole derivatives function by acting as de-repressors of C. trachomatis TrpR. Second, trp operon derepression is profoundly deleterious when infected cells are in an indoledeficient environment, because in the absence of indole, tryptophan synthase deaminates serine to pyruvate and ammonia. We have used biochemical and genetic approaches to demonstrate that expression of wild-type tryptophan synthase is required for the bactericidal production of ammonia. Pertinently, although these indole derivatives de-repress the trpRBA operon of C. trachomatis strains with trpA or trpB mutations, no ammonia is produced, and no deleterious effects are observed. Our studies demonstrate that tryptophan synthase can catalyze the ammonia-generating β-elimination reaction within any live bacterium. Our results also likely explain previous observations demonstrating that the same indole derivatives inhibit the growth of other pathogenic bacterial species, and why high serum levels of these indole derivatives are favorable for the prognosis of diseased conditions associated with bacterial dysbiosis.Chlamydia trachomatis | genital and ocular serovars | tryptophan synthase β-elimination | serine deamination | trp operon de-repression

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Lower Levels of Cervicovaginal Tryptophan Are Associated With Natural Clearance of Chlamydia in Women

Abstract: Chlamydia trachomatis (Ct) infection causes significant morbidity. In vitro studies demonstrate

Cited by 16 publications

References 16 publications

The genital tract and rectal microbiomes: their role in HIV susceptibility and prevention in women

The genital tract and rectal microbiomes: their role in HIV susceptibility and prevention in women

High expression of IDO1 and TGF-β1 during recurrence and post infection clearance with Chlamydia trachomatis, are independent of host IFN-γ response

Ammonia generation by tryptophan synthase drives a key genetic difference between genital and ocular Chlamydia trachomatis isolates

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