scholarly journals Gastrointestinal Coinfection Promotes Chlamydial Pathogenicity in the Genital Tract

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Qi Tian ◽  
Zengzi Zhou ◽  
Luying Wang ◽  
Al-Mutassim Hani Abu-Khdeir ◽  
Zhi Huo ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Experimental Evidence ◽  
Significant Role ◽  
Genital Tract ◽  
Wild Type ◽  
Second Hit ◽  
Pathogenic Mechanisms ◽  
Sexually Transmitted ◽  
Indirect Mechanism

ABSTRACT Sexually transmitted Chlamydia, which can cause fibrotic pathology in women’s genital tracts, is also frequently detected in the gastrointestinal tract. However, the medical significance of the gastrointestinal Chlamydia remains unclear. A murine Chlamydia readily spreads from the mouse genital tract to the gastrointestinal tract while inducing oviduct fibrotic blockage or hydrosalpinx. We previously proposed a two-hit model in which the mouse gastrointestinal Chlamydia might induce the second hit to promote genital tract pathology, and we are now providing experimental evidence for testing the hypothesis. First, chlamydial mutants that are attenuated in inducing hydrosalpinx in the genital tract also reduce their colonization in the gastrointestinal tract, leading to a better correlation of chlamydial induction of hydrosalpinx with chlamydial colonization in the gastrointestinal tract than in the genital tract. Second, intragastric coinoculation with a wild-type Chlamydia rescued an attenuated Chlamydia mutant to induce hydrosalpinx, while the chlamydial mutant infection in the genital tract alone was unable to induce any significant hydrosalpinx. Finally, the coinoculated gastrointestinal Chlamydia failed to directly spread to the genital tract lumen, suggesting that gastrointestinal Chlamydia may promote genital pathology via an indirect mechanism. Thus, we have demonstrated a significant role of gastrointestinal Chlamydia in promoting pathology in the genital tract possibly via an indirect mechanism. This study provides a novel direction/dimension for further investigating chlamydial pathogenic mechanisms.

Gastrointestinal Chlamydia -induced CD8 + T cells promote chlamydial pathogenicity in the female upper genital tract

2021 ◽  
Author(s):  
Qi Tian ◽  
Zengzi Zhou ◽  
Luying Wang ◽  
Xin Sun ◽  
Bernard Arulanandam ◽  
...  
Keyword(s):  
T Cells ◽  
Gastrointestinal Tract ◽  
T Lymphocyte ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Genital Tract ◽  
Wild Type ◽  
Necessary And Sufficient ◽  
Lymphocyte Responses

Chlamydia is known to both ascend to the upper genital tract and spread to the gastrointestinal tract following intravaginal inoculation. The gastrointestinal Chlamydia was recently reported to promote chlamydial pathogenicity in the genital tract since mice intravaginally inoculated with an attenuated Chlamydia , which alone failed to develop pathology in the genital tract, were restored to develop hydrosalpinx by intragastric co-inoculation with wild type Chlamydia . Gastrointestinal Chlamydia promoted hydrosalpinx via an indirect mechanism since Chlamydia in the gut did not directly spread to the genital tract lumen. In the current study, we further investigated the role of CD8 + T cells in the promotion of hydrosalpinx by gastrointestinal Chlamydia . First, we confirmed that intragastric co-inoculation with wild type Chlamydia promoted hydrosalpinx in mice that were inoculated with an attenuated Chlamydia in the genital tract one week earlier. Second, the promotion of hydrosalpinx by intragastrically co-inoculated Chlamydia was blocked by depleting CD8 + T cells. Third, adoptive transfer of the gastrointestinal Chlamydia -induced CD8 + T cells was sufficient for promoting hydrosalpinx in mice that were intravaginally inoculated with an attenuated Chlamydia . These observations have demonstrated that CD8 + T cells induced by gastrointestinal Chlamydia are both necessary and sufficient for promoting hydrosalpinx in the genital tract. The study has laid a foundation for further revealing the mechanisms by which Chlamydia -induced T lymphocyte responses (as a 2 nd hit) promote hydrosalpinx in mice with genital Chlamydia -triggered tubal injury (as a 1 st hit), a continuing effort in testing the two-hit hypothesis as a chlamydial pathogenic mechanism.

Genital mycoplasmas, including Mycoplasma genitalium, as sexually transmitted agents

2002 ◽  
Vol 13 (2) ◽  
pp. 79-85 ◽  
Author(s):  
Anneli Uusküla ◽  
Peter K Kohl
Keyword(s):  
Genital Tract ◽  
Ureaplasma Urealyticum ◽  
Female Genital Tract ◽  
Mycoplasma Species ◽  
Case Control Studies ◽  
Pathogenic Potential ◽  
Intracellular Location ◽  
Main Site ◽  
Sexually Transmitted

Mycoplasmas are the smallest free-living organisms, widespread in nature. Several mycoplasma species have been isolated from humans. For 6 of them: Mycoplasma hominis, Ureaplasma urealyticum, M. primatum, M. genitalium, M. spermatophilum and M. penetrans, the genital tract is the main site of colonization. This review is concentrated on the role of mycoplasmas as sexually transmitted agents, with the emphasis to M. genitalium infections. M. hominis and U. urealyticum are isolated from the genital tract of healthy men and women with considerable frequency. The biological features (attachment properties, possible intracellular location) and experimental inoculation studies of M. genitalium indicate that this mycoplasma has pathogenic potential. Data from case-control studies, looking at men with non-gonococcal urethritis and women with cervicitis, have revealed that M. genitalium behave similarly to Chlamydia trachomatis and have revealed that carriage of M. genitalium and C. trachomatis is usually independent of one another. M. genitalium could be considered as a potential cause of sexually transmitted urethritis in men, including men with persistent or recurrent urethritis. More studies are expected to ascertain the role of M. genitalium in the female genital tract. Evidence-based data are needed to decide whether current non-gonococcal infection treatment principles are applicable or not for M. genitalium infections.

VASP is involved in cAMP-mediated Rac 1 activation in microvascular endothelial cells

2009 ◽  
Vol 296 (3) ◽  
pp. C453-C462 ◽  
Author(s):  
Nicolas Schlegel ◽  
Jens Waschke
Keyword(s):  
Endothelial Cells ◽  
Protective Effect ◽  
Significant Role ◽  
Barrier Properties ◽  
Endothelial Barrier ◽  
Microvascular Endothelial Cells ◽  
Wild Type ◽  
Barrier Functions ◽  
Baseline Levels

Accumulating evidence points to a significant role of vasodilator-stimulated phosphoprotein (VASP) in the maintenance of endothelial barrier functions. We have recently shown that impaired barrier functions in VASP-deficient microvascular myocardial endothelial cells (MyEnd VASP−/−) correlated with decreased Rac 1 activity. To further test the hypothesis that VASP is involved in regulation of Rac 1 activity, we studied cAMP-dependent Rac 1 activation. Both inhibition of Rac 1 activation by NSC-23766 and inhibition of PKA by PKI completely blunted the efficacy of forskolin/rolipram (F/R)-mediated cAMP increase to stabilize barrier functions as revealed by measurements of transendothelial resistance (TER). Because these results indicate that PKA/Rac 1 activation is important for barrier stabilization, we tested this signaling pathway in VASP−/− cells. We found that F/R and isoproterenol reduced permeability measured as FITC-dextran flux across VASP−/− monolayers, but not below baseline levels of wild-type cells (WT). Moreover, cAMP-mediated Rac 1 activation was reduced to ∼50% of WT levels, and both PKA inhibition by PKI and PKA anchoring via A kinase anchoring peptides (AKAPs) by HT31 almost completely abolished Rac 1 activation in VASP−/− and WT endothelium. Accordingly, HT31 significantly reduced F/R-mediated TER increase in WT cells and completely blocked the protective effect of cAMP on endothelial barrier properties. Together, our data underline the significant role of cAMP-mediated Rac 1 activation for endothelial barrier stabilization and demonstrate that both AKAP-mediated PKA anchoring and VASP are required for this process.

The human MDM-2 oncogene is overexpressed in leukemias

Blood ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2617-2623 ◽  
Author(s):  
CE Bueso-Ramos ◽  
Y Yang ◽  
E deLeon ◽  
P McCown ◽  
SA Stass ◽  
...  
Keyword(s):  
Gene Amplification ◽  
Significant Role ◽  
Chromosomal Abnormalities ◽  
P53 Protein ◽  
Cellular Protein ◽  
Wild Type ◽  
Mouse Double Minute ◽  
Tumorigenic Potential ◽  
Prognostic Groups

The human homologue of the mouse double minute 2 (MDM-2) gene codes for a cellular protein that forms a complex with the mutant and wild-type p53 protein and modulates its trans-activation activity. Overexpression of the MDM-2 gene in cells increases their tumorigenic potential and overcomes the growth-suppressive activity of p53. Previous reports have shown that the MDM-2 gene is amplified in approximately one third of human sarcomas. To examine the role of MDM-2 in leukemia, we analyzed MDM-2 gene amplification and mRNA expression in various types of leukemias. We did not detect gene amplification in any of the 48 cases of leukemia that we examined. In contrast, we observed significant MDM- 2 mRNA overexpression in 34 of 64 cases (53%). The level of mRNA overexpression in some cases of leukemias was comparable to that observed in some cases of sarcomas, which demonstrate more than 50-fold MDM-2 gene amplification. Furthermore, we divided these cases into different prognostic groups according to their karyotypic abnormalities. MDM-2 overexpression seemed to be associated with unfavorable chromosomal abnormalities. These findings suggest that the expression of the MDM-2 gene is altered in a significant fraction of human leukemias and MDM-2 may play a significant role in leukemogenesis. In addition, these results suggest that mechanisms other than gene amplification may play a significant role in deregulating the MDM-2 expression.

scholarly journals Nonpathogenic Colonization with Chlamydia in the Gastrointestinal Tract as Oral Vaccination for Inducing Transmucosal Protection

2017 ◽  
Vol 86 (2) ◽  
Author(s):  
Luying Wang ◽  
Cuiming Zhu ◽  
Tianyuan Zhang ◽  
Qi Tian ◽  
Nu Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Gastrointestinal Tract ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Genital Tract ◽  
Genital Tract Infection ◽  
Content Type ◽  
Chlamydia Muridarum ◽  
Class Ii Antigen

ABSTRACTChlamydiahas been detected in the gastrointestinal tracts of humans and animals. We now report that gastrointestinalChlamydia muridarumis able to induce robust transmucosal protection in mice.C. muridarumcolonization in the gastrointestinal tract correlated with both a shortened course ofC. muridarumgenital tract infection and stronger protection against subsequent genital tract challenge infection. Mice preinoculated intragastrically withC. muridarumbecame highly resistant to subsequentC. muridaruminfection in the genital tract, resulting in prevention of pathology in the upper genital tract. The transmucosal protection in the genital tract was rapidly induced, durable, and dependent on major histocompatibility complex (MHC) class II antigen presentation but not MHC class I antigen presentation. Although a deficiency in CD4+T cells only partially reduced the transmucosal protection, depletion of CD4+T cells from B cell-deficient mice completely abolished the protection, suggesting a synergistic role of both CD4+T and B cells in the gastrointestinalC. muridarum-induced transmucosal immunity. However, the same protective immunity did not significantly affectC. muridarumcolonization in the gastrointestinal tract. The long-lasting colonization withC. muridarumwas restricted to the gastrointestinal tract and was nonpathogenic to either gastrointestinal or extragastrointestinal tissues. Furthermore, gastrointestinalC. muridarumdid not alter the gut microbiota or the development of gut mucosal resident memory T cell responses to a nonchlamydial infection. Thus,Chlamydiamay be developed into a safe and orally deliverable replicating vaccine for inducing transmucosal protection.

scholarly journals The Escherichia coli O157 Flagellar Regulatory Gene flhC and Not the Flagellin Gene fliC Impacts Colonization of Cattle

2006 ◽  
Vol 74 (5) ◽  
pp. 2894-2905 ◽  
Author(s):  
Heather S. Dobbin ◽  
Carolyn J. Hovde ◽  
Christopher J. Williams ◽  
Scott A. Minnich
Keyword(s):  
Escherichia Coli ◽  
Gastrointestinal Tract ◽  
Oral Dose ◽  
Regulatory Gene ◽  
Wild Type ◽  
E Coli ◽  
Regulatory Mutant ◽  
The Relationship ◽  
Better Than

ABSTRACT A virulent European Escherichia coli O157:H − isolate is nonmotile due to a 12-bp deletion in the flagellar regulatory gene flhC. To investigate the contribution of flhC in the relationship between E. coli O157:H7 and cattle, we constructed a similar flhC regulatory mutant in the well-characterized strain ATCC 43894. There was no difference in the growth rate between the wild type and this regulatory mutant, but phenotypic arrays showed substrate utilization differences. Survival in the bovine gastrointestinal tract and colonization of the rectoanal junction mucosa were assessed. Mixtures of both strains were given orally or rectally to steers or administered into the rumen of cattle dually cannulated at the rumen and duodenum. One day post-oral dose, most rectal/fecal isolates (74%) were the regulatory mutant, but by 3 days post-oral dose and throughout the 42-day experiment, ≥80% of the isolates were wild type. Among steers given a rectal application of both strains, wild-type isolates were the majority of isolates recovered on all days. The regulatory mutant survived better than the wild type in both the rumen and duodenum. To test the role of motility, a filament mutant (ΔfliC) was constructed and similar cattle experiments were performed. On all days post-oral dose, the majority of isolates (64% to 98%) were the filament mutant. In contrast, both strains were recovered equally post-rectal application. Thus, the regulatory mutant survived passage through the bovine gastrointestinal tract better than the wild type but failed to efficiently colonize cattle, and the requirement of flhC for colonization was not dependent on a functional flagellum.

scholarly journals Appetite regulating genes in zebrafish gut; a gene expression study

2021 ◽  
Author(s):  
Ehsan Pashay Ahi ◽  
Mathilde Brunel ◽  
Emmanouil Tsakoumis ◽  
Junyu Chen ◽  
Monika Schmitz
Keyword(s):  
Gastrointestinal Tract ◽  
Leptin Receptor ◽  
Expression Patterns ◽  
Differentially Expressed ◽  
Wild Type ◽  
Signal Functions ◽  
Multiple Organs ◽  
Normal Feeding ◽  
The Brain

The underlying molecular pathophysiology of feeding disorders, particularly in peripheral organs, is still largely unknown. A range of molecular factors encoded by appetite-regulating genes are already described to control feeding behaviour in the brain. However, the important role of the gastrointestinal tract in the regulation of appetite and feeding in connection to the brain has gained more attention in the recent years. An example of such inter-organ molecular interaction can be the signals mediated by leptin, a key regulator of body weight, food intake and metabolism, with conserved anorexigenic effects in vertebrates. Leptin signal functions through its receptor ( lepr ) in multiple organs, including the brain and the gastrointestinal tract. So far, the regulatory connections between leptin signal and other appetite-regulating genes remain unclear, particularly in the gastrointestinal system. In this study, we used a zebrafish mutant with impaired function of leptin receptor to explore gut expression patterns of appetite-regulating genes, under different feeding conditions (normal feeding, 7-day fasting, 2 and 6-hours refeeding). We compared these expression patterns to those from wild-type zebrafish, in order to identify leptin-dependent differentially expressed genes located in the zebrafish gut. We provide evidence that most appetite-regulating genes are expressed in the zebrafish gut. On one hand, we did not observed significant differences in the expression of orexigenic genes after changes in the feeding condition, and only one orexigenic gene, hcrt , displayed differential expression under impaired leptin signal. On the other hand, we found 8 anorexigenic genes in wild-types ( cart2 , cart3 , dbi , oxt , nmu , nucb2a , pacap and pomc ), as well as 4 genes in lepr mutants ( cart3 , kiss1, kiss1r and nucb2a ), to be differentially expressed in the zebrafish gut after changes in feeding conditions. Most of these genes also showed significant differences in their expression between wild-type and lepr mutant in at least one of the feeding conditions. Finally, we observed that impaired leptin signalling influences potential regulatory connections between anorexigenic genes in zebrafish gut, particularly connections involving cart2 , cart3 , kiss1 , kiss1r , mchr2 , nmu , nucb2a and oxt . Altogether, these transcriptional changes propose a potential role of the gastrointestinal tract in the regulation of feeding through changes in expression of certain anorexigenic genes in zebrafish.

scholarly journals A Genital Infection-Attenuated Chlamydia muridarum Mutant Infects the Gastrointestinal Tract and Protects against Genital Tract Challenge

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Sandra G. Morrison ◽  
Amanda M. Giebel ◽  
Evelyn Toh ◽  
Arkaprabha Banerjee ◽  
David E. Nelson ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Genital Tract ◽  
The United States ◽  
Effective Vaccine ◽  
Genital Infection ◽  
Wild Type ◽  
Gi Tract ◽  
Genital Infections ◽  
Content Type ◽  
Chlamydia Muridarum

ABSTRACT Chlamydia spp. productively infect mucosal epithelial cells of multiple anatomical sites, including the conjunctiva, lungs, gastrointestinal (GI) tract, and urogenital tract. We, and others, previously established that chlamydial GI tropism is mediated by distinct chromosomal and plasmid factors. In this study, we describe a genital infection-attenuated Chlamydia muridarum mutant (GIAM-1) that is profoundly and specifically attenuated in the murine genital tract. GIAM-1 infected the murine GI tract similarly to wild-type (WT) Chlamydia muridarum but did not productively infect the lower genital tract of female mice, ascend to infect the upper genital tract, or cause hydrosalpinx. However, GI infection of mice with GIAM-1 elicited a transmucosal immune response that protected against subsequent genital challenge with WT Chlamydia muridarum. Collectively, our results demonstrate that chlamydia mutants that are profoundly attenuated for specific organ tissues can be derived and demonstrate that live-attenuated vaccine strains that infect the GI tract, but do not elicit genital tract disease, could be used to protect against chlamydia genital tract infection and disease. IMPORTANCE Chlamydia is the most common sexually transmitted bacterial infection in the United States. Most chlamydia genital infections resolve without serious consequences; however, untreated infection in women can cause pelvic inflammatory disease and infertility. Antibiotics are very effective in treating chlamydia, but most genital infections in both men and women are asymptomatic and go undiagnosed. Therefore, there is a critical need for an effective vaccine. In this work, we show that a mutant chlamydia strain, having substantially reduced virulence for genital infection, colonizes the gastrointestinal tract and produces robust immunity to genital challenge with fully virulent wild-type chlamydia. These results are an important advance in understanding chlamydial virulence and provide compelling evidence that safe and effective live-attenuated chlamydia vaccines may be feasible.

scholarly journals Chlamydia muridarum with Mutations in Chromosomal Genes tc0237 and/or tc0668 Is Deficient in Colonizing the Mouse Gastrointestinal Tract

2017 ◽  
Vol 85 (8) ◽  
Author(s):  
Lili Shao ◽  
Tianyuan Zhang ◽  
Quanzhong Liu ◽  
Jie Wang ◽  
Guangming Zhong
Keyword(s):  
Gastrointestinal Tract ◽  
Genital Tract ◽  
Potential Role ◽  
Wild Type ◽  
Content Type ◽  
Chlamydia Muridarum ◽  
Primary Function ◽  
Ascending Infection ◽  
Chromosomal Genes

ABSTRACT Chlamydiae colonize the gastrointestinal tracts of both animals and humans. However, their medical significance remains unknown. We have previously shown that wild-type Chlamydia muridarum spreads to and establishes stable colonization of the gastrointestinal tract following intravaginal inoculation. In the present study, we found that C. muridarum with mutations in chromosomal genes tc0237 and/or tc0668 was defective in spreading to the mouse gastrointestinal tract, which correlated with its attenuated pathogenicity in the upper genital tract. This correlation was more consistent than that of chlamydial pathogenicity with ascending infection in the genital tract, since attenuated C. muridarum spread significantly less to the gastrointestinal tract but maintained robust ascending infection of the upper genital tract. Transcervical inoculation further confirmed the correlation between C. muridarum spreading to the gastrointestinal tract and its pathogenicity in the upper genital tract. Finally, defective spreading of C. muridarum mutants was due to their inability to colonize the gastrointestinal tract since intragastric inoculation did not rescue the mutants' colonization. Thus, promoting C. muridarum colonization of the gastrointestinal tract may represent a primary function of the TC0237 and TC0668 proteins. Correlation of chlamydial colonization of the gastrointestinal tract with chlamydial pathogenicity in the upper genital tract suggests a potential role for gastrointestinal chlamydiae in genital tract pathogenicity.

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