scholarly journals Reversible Inhibition of Chlamydia trachomatis Infection in Epithelial Cells Due to Stimulation of P2X4Receptors

2012 ◽  
Vol 80 (12) ◽  
pp. 4232-4238 ◽  
Author(s):  
Matthew A. Pettengill ◽  
Camila Marques-da-Silva ◽  
Maria Luisa Avila ◽  
Suellen d'Arc dos Santos Oliveira ◽  
Verissa W. Lam ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Epithelial Cells ◽  
Bacterial Infections ◽  
Degradation Products ◽  
Microbial Pathogens ◽  
Content Type ◽  
Chlamydia Trachomatis Infection ◽  
Extracellular Milieu ◽  
Infected Cells ◽  
Stimulation Of

ABSTRACTBacterial infections of the mucosal epithelium are a major cause of human disease. The prolonged presence of microbial pathogens stimulates inflammation of the local tissues, which leads to changes in the molecular composition of the extracellular milieu. A well-characterized molecule that is released to the extracellular milieu by stressed or infected cells is extracellular ATP and its ecto-enzymatic degradation products, which function as signaling molecules through ligation of purinergic receptors. There has been little information, however, on the effects of the extracellular metabolites on bacterial growth in inflamed tissues. Millimolar concentrations of ATP have been previously shown to inhibit irreversibly bacterial infection through ligation of P2X7receptors. We show here that the proinflammatory mediator, ATP, is released fromChlamydia trachomatis-infected epithelial cells. Moreover, further stimulation of the infected cells with micromolar extracellular ADP or ATP significantly impairs the growth of the bacteria, with a profile characteristic of the involvement of P2X4receptors. A specific role for P2X4was confirmed using cells overexpressing P2X4. The chlamydiae remain viable and return to normal growth kinetics after removal of the extracellular stimulus, similar to responses previously described for persistence of chlamydial infection.

scholarly journals Transcriptional Profiling of Human Epithelial Cells Infected with Plasmid-Bearing and Plasmid-Deficient Chlamydia trachomatis

2014 ◽  
Vol 83 (2) ◽  
pp. 534-543 ◽  
Author(s):  
Stephen F. Porcella ◽  
John H. Carlson ◽  
Daniel E. Sturdevant ◽  
Gail L. Sturdevant ◽  
Kishore Kanakabandi ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Epithelial Cells ◽  
Transcriptional Profiling ◽  
Colony Stimulating Factor ◽  
Content Type ◽  
Human Epithelial Cells ◽  
Infected Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Chlamydia trachomatisis an obligate intracellular epitheliotropic bacterial pathogen of humans. Infection of the eye can result in trachoma, the leading cause of preventable blindness in the world. The pathophysiology of blinding trachoma is driven by multiple episodes of reinfection of conjunctival epithelial cells, producing an intense chronic inflammatory response resulting in submucosal tissue remodeling and scarring. Recent reports have shown that infection with trachoma organisms lacking the cryptic chlamydial plasmid is highly attenuated in macaque eyes, a relevant experimental model of human trachoma infection. To better understand the molecular basis of plasmid-mediated infection attenuation and the potential modulation of host immunity, we conducted transcriptional profiling of human epithelial cells infected withC. trachomatisplasmid-bearing (A2497) and plasmid-deficient (A2497P−) organisms. Infection of human epithelial cells with either strain increased the expression of host genes coding for proinflammatory (granulocyte-macrophage colony-stimulating factor [GM-CSF], macrophage colony-stimulating factor [MCSF], interleukin-6 [IL-6], IL-8, IL-1α, CXCL1, CXCL2, CXCL3, intercellular adhesion molecule 1 [ICAM1]), chemoattraction (CCL20, CCL5, CXCL10), immune suppression (PD-L1, NFKB1B, TNFAIP3, CGB), apoptosis (CASP9, FAS, IL-24), and cell growth and fibrosis (EGR1 and IL-20) proteins. Statistically significant increases in the levels of expression of many of these genes were found in A2497-infected cells compared to the levels of expression in A2497P−-infected cells. Our findings suggest that the chlamydial plasmid plays a focal role in the host cell inflammatory response to infection and immune avoidance. These results provide new insights into the role of the chlamydial plasmid as a chlamydial virulence factor and its contributions to trachoma pathogenesis.

scholarly journals Differential Regulation of Inflammatory Cytokine Secretion by Human Dendritic Cells upon Chlamydia trachomatis Infection

2004 ◽  
Vol 72 (12) ◽  
pp. 7231-7239 ◽  
Author(s):  
Ana Gervassi ◽  
Mark R. Alderson ◽  
Robert Suchland ◽  
Jean François Maisonneuve ◽  
Kenneth H. Grabstein ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Chlamydia Trachomatis ◽  
Wide Spectrum ◽  
Cytokine Secretion ◽  
Host Cells ◽  
Microbial Pathogens ◽  
Potential Contribution ◽  
Necrosis Factor Alpha ◽  
Chlamydia Trachomatis Infection ◽  
Tnf Α

ABSTRACT Chlamydia trachomatis is an obligate intracellular gram-negative bacterium responsible for a wide spectrum of diseases in humans. Both genital and ocular C. trachomatis infections are associated with tissue inflammation and pathology. Dendritic cells (DC) play an important role in both innate and adaptive immune responses to microbial pathogens and are a source of inflammatory cytokines. To determine the potential contribution of DC to the inflammatory process, human DC were infected with C. trachomatis serovar E or L2. Both C. trachomatis serovars were found to infect and replicate in DC. Upon infection, DC up-regulated the expression of costimulatory (B7-1) and cell adhesion (ICAM-1) molecules. Furthermore, chlamydial infection induced the secretion of interleukin-1β (IL-1β), IL-6, IL-8, IL-12p70, IL-18, and tumor necrosis factor alpha (TNF-α). The mechanisms involved in Chlamydia-induced IL-1β and IL-18 secretion differed from those of the other cytokines. Chlamydia-induced IL-1β and IL-18 secretion required infection with viable bacteria and was associated with the Chlamydia-induced activation of caspase-1 in infected host cells. In contrast, TNF-α and IL-6 secretion did not require that the Chlamydia be viable, suggesting that there are at least two mechanisms involved in the Chlamydia-induced cytokine secretion in DC. Interestingly, an antibody to Toll-like receptor 4 inhibited Chlamydia-induced IL-1β, IL-6, and TNF-α secretion. The data herein demonstrate that DC can be infected by human C. trachomatis serovars and that chlamydial components regulate the secretion of various cytokines in DC. Collectively, these data suggest that DC play a role in the inflammatory processes caused by chlamydial infections.

scholarly journals Chlamydia trachomatis infection: a challenge for the urologist

2011 ◽  
Vol 2 (1) ◽  
pp. 14 ◽  
Author(s):  
Tommaso Cai ◽  
Sandra Mazzoli ◽  
Nicola Mondaini ◽  
Gianni Malossini ◽  
Riccardo Bartoletti
Keyword(s):  
Chlamydia Trachomatis ◽  
Bacterial Infections ◽  
Reproductive Tract ◽  
Diagnosis And Treatment ◽  
Everyday Clinical Practice ◽  
Chlamydia Trachomatis Infection ◽  
Sexually Transmitted ◽  
New Findings ◽  
Asymptomatic Infections

<p>The role of <em>Chlamydia trachomatis</em> (Ct) in everyday clinical practice is now on the increase because Ct infections are the most prevalent sexually transmitted bacterial infections worldwide. Ct can cause urethritis, cervicitis, pharyngitis, or epididymitis, although asymptomatic infections are quite common. Ct infection remains asymptomatic in approximately 50% of infected men and 70% of infected women, with risk for reproductive tract sequelae both in women and men. A proper early diagnosis and treatment is essential in order to prevent persistent consequences. An accurate comprehension of the pathology, diagnosis and treatment of this entity is essential for the urologist. We review the literature about the new findings in diagnosis and treatment of Ct infection in sexually active young men.</p>

scholarly journals Interleukin-7 Produced by Intestinal Epithelial Cells in Response to Citrobacter rodentium Infection Plays a Major Role in Innate Immunity against This Pathogen

2015 ◽  
Vol 83 (8) ◽  
pp. 3213-3223 ◽  
Author(s):  
Wei Zhang ◽  
Jiang-Yuan Du ◽  
Qing Yu ◽  
Jun-O Jin
Keyword(s):  
Epithelial Cells ◽  
Protective Immunity ◽  
Bacterial Infections ◽  
Intestinal Epithelial Cells ◽  
Intestinal Damage ◽  
Intestinal Epithelial ◽  
Citrobacter Rodentium ◽  
Content Type ◽  
Interleukin 7

Interleukin-7 (IL-7) engages multiple mechanisms to overcome chronic viral infections, but the role of IL-7 in bacterial infections, especially enteric bacterial infections, remains unclear. Here we characterized the previously unexplored role of IL-7 in the innate immune response to the attaching and effacing bacteriumCitrobacter rodentium.C. rodentiuminfection induced IL-7 production from intestinal epithelial cells (IECs). IL-7 production from IECs in response toC. rodentiumwas dependent on gamma interferon (IFN-γ)-producing NK1.1+cells and IL-12. Treatment with anti-IL-7Rα antibody duringC. rodentiuminfection resulted in a higher bacterial burden, enhanced intestinal damage, and greater weight loss and mortality than observed with the control IgG treatment. IEC-produced IL-7 was only essential for protective immunity againstC. rodentiumduring the first 6 days after infection. An impaired bacterial clearance upon IL-7Rα blockade was associated with a significant decrease in macrophage accumulation and activation in the colon. Moreover,C. rodentium-induced expansion and activation of intestinal CD4+lymphoid tissue inducer (LTi) cells was completely abrogated by IL-7Rα blockade. Collectively, these data demonstrate that IL-7 is produced by IECs in response toC. rodentiuminfection and plays a critical role in the protective immunity against this intestinal attaching and effacing bacterium.

scholarly journals Persistent Chlamydia trachomatis Infection of HeLa Cells Mediates Apoptosis Resistance through a Chlamydia Protease-Like Activity Factor-Independent Mechanism and Induces High Mobility Group Box 1 Release

2011 ◽  
Vol 80 (1) ◽  
pp. 195-205 ◽  
Author(s):  
Jürgen Rödel ◽  
Christina Große ◽  
Hangxing Yu ◽  
Katharina Wolf ◽  
Gordon P. Otto ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Host Cell ◽  
Hela Cells ◽  
Persistent Infection ◽  
High Mobility ◽  
Apoptosis Resistance ◽  
Content Type ◽  
Activity Factor ◽  
Infected Cells ◽  
Ifn Γ

ABSTRACTIntracellular persistence ofChlamydia trachomatishas been implicated in the development of chronic infection that can result in pelvic inflammatory disease and tubal sterility. By inhibition of host cell apoptosis, chlamydiae have evolved a strategy to maintain the intracellular environment for replication and persistence. Both antiapoptotic host cell-derived factors and the chlamydial protease-like activity factor (CPAF) are involved inChlamydia-mediated apoptosis resistance. Here, we show that in HeLa cells infected with gamma interferon (IFN-γ)-induced persistentC. trachomatisserovar D, the expression of CPAF is downregulated, and proapoptotic protease substrates are not cleaved. Persistent infection protected HeLa cells from apoptosis when they were exposed to staurosporine. Small-interfering RNA-mediated inhibition of myeloid cell leukemia 1 (Mcl-1) protein upregulation sensitized persistently infected cells for apoptosis. The inhibitor of apoptosis protein 2 (IAP-2) seems not to be relevant in this context because IAP-2 protein was not induced in response to IFN-γ treatment. Although apoptosis was inhibited, persistent infection caused cell membrane disintegration, as measured by the increased release of cytokeratin 18 from HeLa cells. Moreover, persistently infected cells released significantly increased amounts of high mobility group box 1 (HMGB1) protein which represents a proinflammatory damage-associated pattern molecule. The data of this study suggest that cells infected with persistentC. trachomatisare protected from apoptosis independently of CPAF but may promote chronic inflammation through HMGB1 release.

scholarly journals Activation of Lipid Metabolism Contributes to Interleukin-8 Production during Chlamydia trachomatis Infection of Cervical Epithelial Cells

2005 ◽  
Vol 73 (7) ◽  
pp. 4017-4024 ◽  
Author(s):  
Elaine Y. Fukuda ◽  
Sonya P. Lad ◽  
David P. Mikolon ◽  
Milena Iacobelli-Martinez ◽  
Erguang Li
Keyword(s):  
Lipid Metabolism ◽  
Chlamydia Trachomatis ◽  
Epithelial Cells ◽  
Mononuclear Cells ◽  
Interleukin 8 ◽  
Protein Activity ◽  
Peripheral Blood Mononuclear ◽  
Chemokine Production ◽  
Chlamydia Trachomatis Infection ◽  
Parasitic Pathogens

ABSTRACT Chlamydia trachomatis infection is the most common cause of bacterial sexually transmitted diseases. Infection of the urogenital tract by C. trachomatis causes chronic inflammation and related clinical complications. Unlike other invasive bacteria that induce a rapid cytokine/chemokine production, chlamydial infection induces delayed inflammatory response and proinflammatory chemokine production that is dependent on bacterial growth. We present data here to show that the lipid metabolism required for chlamydial growth contributes to Chlamydia-induced proinflammatory chemokine production. By gene microarray profiling, validated with biochemical studies, we found that C. trachomatis LGV2 selectively upregulated PTGS2 (COX2) and PTGER4 (EP4) in cervical epithelial HeLa 229 cells. COX2 is an enzyme that catalyzes the rate-limiting step of arachidonic acid conversion to prostaglandins, including prostaglandin E2 (PGE2) and other eicosanoids, whereas EP4 is a subtype of cell surface receptors for PGE2. We show that Chlamydia infection induced COX2 protein expression in both epithelial cells and peripheral blood mononuclear cells and promoted PGE2 release. Exogenous PGE2 was able to induce interleukin-8 release in HeLa 229 epithelial cells. Finally, we demonstrated that interleukin-8 induction by Chlamydia infection or PGE2 treatment was dependent on extracellular signal-regulated kinase/mitogen-activated protein activity. Together, these data demonstrate that the host lipid remodeling process required for chlamydial growth contributes to proinflammatory chemokine production. This study also highlights the importance of maintaining a balanced habitat for parasitic pathogens as obligate intracellular organisms.

scholarly journals Cellular Pharmacokinetics and Intracellular Activity of Gepotidacin againstStaphylococcus aureusIsolates with Different Resistance Phenotypes in Models of Cultured Phagocytic Cells

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Frédéric Peyrusson ◽  
Paul M. Tulkens ◽  
Françoise Van Bambeke
Keyword(s):  
Bacterial Infections ◽  
Maximum Effect ◽  
Cell Fractionation ◽  
Phagocytic Cells ◽  
Content Type ◽  
Cellular Pharmacokinetics ◽  
Extracellular Concentration ◽  
Infected Cells ◽  
Maximal Reduction

ABSTRACTGepotidacin (GSK2140944), a novel triazaacenaphthylene bacterial topoisomerase inhibitor, is currently in clinical development for the treatment of bacterial infections. This study examinedin vitroits activity against intracellularStaphylococcus aureus(involved in the persistent character of skin and skin structure infections) by use of a pharmacodynamic model and in relation to cellular pharmacokinetics in phagocytic cells. Compared to oxacillin, vancomycin, linezolid, daptomycin, azithromycin, and moxifloxacin, gepotidacin was (i) more potent intracellularly (the apparent bacteriostatic concentration [Cs] was reached at an extracellular concentration about 0.7× its MIC and was not affected by mechanisms of resistance to the comparators) and (ii) caused a maximal reduction of the intracellular burden (maximum effect) of about −1.6 log10CFU (which was better than that caused by linezolid, macrolides, and daptomycin and similar to that caused by moxifloxacin). After 24 h of incubation of infected cells with antibiotics at 100× their MIC, the intracellular persisting fraction was <0.1% with moxifloxacin, 0.5% with gepotidacin, and >1% with the other drugs. The accumulation and efflux of gepotidacin in phagocytes were very fast (kinandkout, ∼0.3 min−1; the plateau was reached within 15 min) but modest (intracellular concentration-to-extracellular concentration ratio, ∼1.6). In cell fractionation studies, about 40 to 60% of the drug was recovered in the soluble fraction and ∼40% was associated with lysosomes in uninfected cells. In infected cells, about 20% of cell-associated gepotidacin was recovered in a sedimentable fraction that also contained bacteria. This study highlights the potential for further study of gepotidacin to fight infections where intracellular niches may play a determining role in bacterial persistence and relapses.

scholarly journals Spider Venom Peptides for Gene Therapy of Chlamydia Infection

2011 ◽  
Vol 55 (11) ◽  
pp. 5367-5369 ◽  
Author(s):  
Vassili N. Lazarev ◽  
Nadezhda F. Polina ◽  
Marina M. Shkarupeta ◽  
Elena S. Kostrjukova ◽  
Alexander A. Vassilevski ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Chlamydia Trachomatis ◽  
Antimicrobial Peptides ◽  
Spider Venom ◽  
Hek293 Cells ◽  
Chlamydia Infection ◽  
Plasmid Vectors ◽  
Content Type ◽  
Venom Peptides ◽  
Infected Cells

ABSTRACTSpider venoms are vast natural pharmacopoeias selected by evolution. The venom of the ant spiderLachesana tarabaevicontains a wide variety of antimicrobial peptides. We tested six of them (latarcins 1, 2a, 3a, 4b, 5, and cytoinsectotoxin 1a) for their ability to suppressChlamydia trachomatisinfection. HEK293 cells were transfected with plasmid vectors harboring the genes of the selected peptides. Controlled expression of the transgenes led to a significant decrease ofC. trachomatisviability inside the infected cells.

scholarly journals Staphylococcus aureus Phenol-Soluble Modulins Impair Interleukin Expression in Bovine Mammary Epithelial Cells

2016 ◽  
Vol 84 (6) ◽  
pp. 1682-1692 ◽  
Author(s):  
Martine Deplanche ◽  
Ludmila Alekseeva ◽  
Ksenia Semenovskaya ◽  
Chih-Lung Fu ◽  
Frederic Dessauge ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mammary Gland ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Dendritic Cell Maturation ◽  
Mammary Epithelial ◽  
Content Type ◽  
Bovine Mammary Epithelial Cells ◽  
E Coli ◽  
Infected Cells

The role of the recently described interleukin-32 (IL-32) inStaphylococcus aureus-induced mastitis, an inflammation of the mammary gland, is unclear. We determined expression of IL-32, IL-6, and IL-8 inS. aureus- andEscherichia coli-infected bovine mammary gland epithelial cells. Using live bacteria, we found that inS. aureus-infected cells, induction of IL-6 and IL-8 expression was less pronounced than inE. coli-infected cells. Notably, IL-32 expression was decreased inS. aureus-infected cells, while it was increased inE. coli-infected cells. We identified the staphylococcal phenol-soluble modulin (PSM) peptides as key contributors to these effects, as IL-32, IL-6, and IL-8 expression by epithelial cells exposed topsmmutant strains was significantly increased compared to that in cells exposed to the isogenicS. aureuswild-type strain, indicating that PSMs inhibit the production of these interleukins. The use of genetically complemented strains confirmed this observation. Inasmuch as the decreased expression of IL-32, which is involved in dendritic cell maturation, impairs immune responses, our results support a PSM-dependent mechanism that allows for the development of chronicS. aureus-related mastitis.

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