Morphologic and molecular evaluation of Chlamydia trachomatis growth in human endocervix reveals distinct growth patterns

Lewis, Maria E.; Belland, Robert J.; AbdelRahman, Yasser M.; Beatty, Wandy L.; Aiyar, Ashok; Zea, Arnold H.; Greene, Sheila; Marrero, Luis; Buckner, Lyndsey R.; Tate, David J.; McGowin, Chris L.; Kozlowski, Pamela A.; O’Brien, Michelle; Lillis, Rebecca A.; Martín, David H.; Quayle, Alison J.

doi:10.3389/fcimb.2014.00071

Cited by 78 publications

(83 citation statements)

References 62 publications

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“…There are studies that have presented evidence of C. trachomatis DNA or antigens being present in the tubal material of women with tubal infertility or ectopic pregnancy or salpingitis, supporting the idea that organism persistence in some form occurs in vivo (127,(134)(135)(136). Recently, morphologies consistent with laboratory models of persistence were observed in endocervix samples associated with IFN-␥, further supporting the likely in vivo relevance of laboratory models of persistence (55). It is difficult to determine if chlamydial persistence leading to pathology has always occurred.…”

Section: Ascensionmentioning

confidence: 60%

“…While ectopic pregnancy is not only a Chlamydia-related pathology, a study by Balasubramaniam et al that found that levels of the cytokines IL-8 and IL-6 were significantly upregulated in the fallopian tubes immediately at the location of implantation of ectopic pregnancy but not in the fallopian tubes of women undergoing benign hysterectomy (54). A very recent study found that differences in IFN-␥ levels correlated with differences in the chlamydial cellular morphologies at the cervix when comparing two patients (55). In summary, the consistent findings of these studies are that IFN-␥, IL-6, IL-1, IL-8, and high antibody responses to some antigens are associated with chlamydial responses in the reproductive tracts of infertile women and Chlamydia-infected women (a notable caveat being that much of the evidence is from uncomplicated infections).…”

Section: Immune Responses From Reproductive Sites and Tissuesmentioning

confidence: 99%

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Human and Pathogen Factors Associated with Chlamydia trachomatis-Related Infertility in Women

et al. 2015

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SUMMARY Chlamydia trachomatis is the most common bacterial sexually transmitted pathogen worldwide. Infection can result in serious reproductive pathologies, including pelvic inflammatory disease, ectopic pregnancy, and infertility, in women. However, the processes that result in these reproductive pathologies have not been well defined. Here we review the evidence for the human disease burden of these chlamydial reproductive pathologies. We then review human-based evidence that links Chlamydia with reproductive pathologies in women. We present data supporting the idea that host, immunological, epidemiological, and pathogen factors may all contribute to the development of infertility. Specifically, we review the existing evidence that host and pathogen genotypes, host hormone status, age of sexual debut, sexual behavior, coinfections, and repeat infections are all likely to be contributory factors in development of infertility. Pathogen factors such as infectious burden, treatment failure, and tissue tropisms or ascension capacity are also potential contributory factors. We present four possible processes of pathology development and how these processes are supported by the published data. We highlight the limitations of the evidence and propose future studies that could improve our understanding of how chlamydial infertility in women occurs and possible future interventions to reduce this disease burden.

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Section: Ascensionmentioning

confidence: 60%

Section: Immune Responses From Reproductive Sites and Tissuesmentioning

confidence: 99%

Human and Pathogen Factors Associated with Chlamydia trachomatis-Related Infertility in Women

et al. 2015

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“…(25,(28)(29)(30). Moreover, indole can be detected in vaginal secretions from women with BV and aberrant RBs were observed in cervical scrapings from one patient with C. trachomatis (3). This specimen produced few infectious EBs but contained a high Chlamydia genome load, suggesting that most of the genomes corresponded to persistent organisms (3).…”

mentioning

confidence: 99%

“…Maturing RBs then redifferentiate back to EBs and exit the host cell via lysis or extrusion (2). Morphologically aberrant RBs have been observed in clinical specimens (3). This abnormal developmental cycle can be recapitulated in a laboratory setting by exposing C. trachomatis to various stressors such as host cytokines (4)(5)(6), excess amino acids (7), iron deficiency (8,9), virus coinfections (10), and antibiotics (11,12) (reviewed in reference 13).…”

mentioning

confidence: 99%

Beyond Tryptophan Synthase: Identification of Genes That Contribute to Chlamydia trachomatis Survival during Gamma Interferon-Induced Persistence and Reactivation

et al. 2016

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cChlamydia trachomatis can enter a viable but nonculturable state in vitro termed persistence. A common feature of C. trachomatis persistence models is that reticulate bodies fail to divide and make few infectious progeny until the persistence-inducing stressor is removed. One model of persistence that has relevance to human disease involves tryptophan limitation mediated by the host enzyme indoleamine 2,3-dioxygenase, which converts L-tryptophan to N-formylkynurenine. Genital C. trachomatis strains can counter tryptophan limitation because they encode a tryptophan-synthesizing enzyme. Tryptophan synthase is the only enzyme that has been confirmed to play a role in interferon gamma (IFN-␥)-induced persistence, although profound changes in chlamydial physiology and gene expression occur in the presence of persistence-inducing stressors. Thus, we screened a population of mutagenized C. trachomatis strains for mutants that failed to reactivate from IFN-␥-induced persistence. Six mutants were identified, and the mutations linked to the persistence phenotype in three of these were successfully mapped. One mutant had a missense mutation in tryptophan synthase; however, this mutant behaved differently from previously described synthase null mutants. Two hypothetical genes of unknown function, ctl0225 and ctl0694, were also identified and may be involved in amino acid transport and DNA damage repair, respectively. Our results indicate that C. trachomatis utilizes functionally diverse genes to mediate survival during and reactivation from persistence in HeLa cells. Chlamydia trachomatis has a characteristic biphasic developmental cycle in cell culture (1). The two dominant chlamydial forms are elementary bodies (EBs) and reticulate bodies (RBs) (1). EBs represent the infectious, nonreplicative form capable of invading host cells (1). Following entry, EBs differentiate into RBs that replicate inside parasitophorous vacuoles termed inclusions (1). Maturing RBs then redifferentiate back to EBs and exit the host cell via lysis or extrusion (2). Morphologically aberrant RBs have been observed in clinical specimens (3). This abnormal developmental cycle can be recapitulated in a laboratory setting by exposing C. trachomatis to various stressors such as host cytokines (4-6), excess amino acids (7), iron deficiency (8, 9), virus coinfections (10), and antibiotics (11, 12) (reviewed in reference 13). Under these conditions, normal C. trachomatis RBs can transition into persistent forms that do not divide, are enlarged, and have aberrant morphology (13). Upon removal of the persistence-inducing stressor, RBs transition back into normal RBs and continue normal development (13). Aberrant RB morphology is a shared feature of multiple C. trachomatis persistence models and may reflect activation of a common stress response program (13). Thus, characterizing how C. trachomatis enters, survives, and reactivates from persistence could reveal new insights into chlamydial pathogenesis.The Th1 cytokine interferon gamma (IFN-␥) can induce dif...

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“…Persistence in vitro can be induced in cell culture by a variety of methods, including interferon gamma (IFN-␥) treatment of infected human host cells (14), iron starvation via chelation (15,16), and amino acid starvation (17)(18)(19). Of these, IFN-␥-mediated persistence is the most studied and likely the most relevant to in vivo infections (20). The means by which IFN-␥ induces persistence in Chlamydia is well characterized (14,21,22).…”

mentioning

confidence: 99%

Tryptophan Codon-Dependent Transcription in Chlamydia pneumoniae during Gamma Interferon-Mediated Tryptophan Limitation

2016

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In evolving to an obligate intracellular niche, Chlamydia has streamlined its genome by eliminating superfluous genes as it relies on the host cell for a variety of nutritional needs like amino acids. However, Chlamydia can experience amino acid starvation when the human host cell in which the bacteria reside is exposed to interferon gamma (IFN-␥), which leads to a tryptophan (Trp)-limiting environment via induction of the enzyme indoleamine-2,3-dioxygenase (IDO). The stringent response is used to respond to amino acid starvation in most bacteria but is missing from Chlamydia. Thus, how Chlamydia, a Trp auxotroph, responds to Trp starvation in the absence of a stringent response is an intriguing question. We previously observed that C. pneumoniae responds to this stress by globally increasing transcription while globally decreasing translation, an unusual response. Here, we sought to understand this and hypothesized that the Trp codon content of a given gene would determine its transcription level. We quantified transcripts from C. pneumoniae genes that were either rich or poor in Trp codons and found that Trp codon-rich transcripts were increased, whereas those that lacked Trp codons were unchanged or even decreased. There were exceptions, and these involved operons or large genes with multiple Trp codons: downstream transcripts were less abundant after Trp codon-rich sequences. These data suggest that ribosome stalling on Trp codons causes a negative polar effect on downstream sequences. Finally, reassessing previous C. pneumoniae microarray data based on codon content, we found that upregulated transcripts were enriched in Trp codons, thus supporting our hypothesis. Chlamydia is an obligate intracellular bacterial pathogen that causes a range of illnesses in humans and animals (1-4). It alternates between functionally and morphologically distinct forms during its developmental cycle (see reference 5 for review). The elementary body (EB) mediates attachment and internalization into a susceptible host cell, whereas the reticulate body (RB) grows and divides within a membrane-bound pathogen-specified parasitic organelle termed an inclusion (6). In evolving to obligate intracellular parasitism, Chlamydia has streamlined its genome by eliminating superfluous pathways and genes (7). Conversely, if Chlamydia has maintained a set of genes, then it is likely important for the bacterium.There are two primary species of Chlamydia that cause significant disease in humans: C. pneumoniae and C. trachomatis. Many chlamydial infections are often unrecognized and asymptomatic, and failure to treat these infections can lead to chronic sequelae. For C. trachomatis, these sequelae can include pelvic inflammatory disease, tubal factor infertility, and reactive arthritis (8, 9). C. pneumoniae has been associated with a number of chronic conditions, including atherosclerosis and adult-onset asthma among others (10, 11). One possible explanation for asymptomatic chlamydial infections may be due to the ability of the organism to ente...

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Morphologic and molecular evaluation of Chlamydia trachomatis growth in human endocervix reveals distinct growth patterns

Cited by 78 publications

References 62 publications

Human and Pathogen Factors Associated with Chlamydia trachomatis-Related Infertility in Women

Human and Pathogen Factors Associated with Chlamydia trachomatis-Related Infertility in Women

Beyond Tryptophan Synthase: Identification of Genes That Contribute to Chlamydia trachomatis Survival during Gamma Interferon-Induced Persistence and Reactivation

Tryptophan Codon-Dependent Transcription in Chlamydia pneumoniae during Gamma Interferon-Mediated Tryptophan Limitation

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