scholarly journals Stromal Fibroblasts Drive Host Inflammatory Responses That Are Dependent onChlamydia trachomatisStrain Type and Likely Influence Disease Outcomes

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Amber Leah Jolly ◽  
Sameeha Rau ◽  
Anmol K. Chadha ◽  
Ekhlas Ahmed Abdulraheem ◽  
Deborah Dean
Keyword(s):  
Chlamydia Trachomatis ◽  
Epithelial Cells ◽  
Genital Tract ◽  
Inflammatory Responses ◽  
Infection Rates ◽  
Progeny Production ◽  
Content Type ◽  
Disease Outcomes ◽  
Primary Fibroblasts ◽  
Strain Type

ABSTRACTChlamydia trachomatisocular strains cause a blinding disease known as trachoma. These strains rarely cause urogenital infections and are not found in the upper genital tract or rectum. Urogenital strains are responsible for a self-limited conjunctivitis and the sequelae of infertility, ectopic pregnancy, and hemorrhagic proctitis. However, the differential cellular responses that drive these clinically observed disease outcomes are not completely understood. Primary conjunctival, endocervical, and endometrial epithelial and stromal fibroblast cells, HeLa229 cells, and immortalized conjunctival epithelial (HCjE) cells were infected with the ocular A/Har-13 (A) and Ba/Apache-2 (Ba) strains and urogenital D/UW-3 (D) and E/Bour (E) strains. Infection rates, progeny production, and cytokine/chemokine secretion levels were evaluated in comparison with those in uninfected cells. All strain types infected all cell types with similar levels of efficacy and development. However, progeny production levels differed among primary cells: Ba produced significantly more progeny than E in endocervical and endometrial fibroblasts, while A progeny were less abundant than E progeny.C.trachomatisinfection of primary epithelial cells elicited an increase in pro- and anti-inflammatory mediators compared to levels in uninfected cells, but there were no significant differences by strain type. In contrast, for primary fibroblasts, ocular strains elicited significant increases in the pro- and anti-inflammatory mediators macrophage inflammatory protein (MIP)-1β, thymus- and activation-regulated chemokine (TARC), interleukin (IL)-2, IL-12p70, and interferon gamma-induced protein 10 (IP-10) compared to levels in urogenital strains, while urogenital strains elicited a distinct and significant increase in the proinflammatory mediators IL-1α, IL-1β, IL-8, gamma interferon (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Our data indicate that primary fibroblasts, not epithelial cells, drive host inflammatory responses that are dependent on strain type and likely influence disease outcomes, establishing their importance as a novel model for studies ofC. trachomatisdisease pathogenesis.IMPORTANCEChlamydia trachomatisis a human pathogen and the leading cause of preventable blindness and sexually transmitted diseases in the world. CertainC. trachomatisstrains cause ocular disease, while others cause upper genital tract pathology. However, little is known about the cellular or immunologic basis for these differences. Here, we compared the abilities of the strain types to infect, replicate, and initiate an immune response in primary human ocular and urogenital epithelial cells, as well as in fibroblasts from the underlying stroma. While there were no significant differences in infection rates or intracellular growth for any strain in any cell type, proinflammatory responses were driven not by the epithelial cells but by fibroblasts and were distinct between ocular and urogenital strains. Our findings suggest that primary fibroblasts are a novel and more appropriate model for studies of immune responses that will expand our understanding of the differential pathological disease outcomes caused by variousC. trachomatisstrain types.

scholarly journals Infection of Hysterectomized Mice with Chlamydia muridarum and Chlamydia trachomatis

2017 ◽  
Vol 85 (7) ◽  
Author(s):  
Chunfu Yang ◽  
William M. Whitmire ◽  
Gail L. Sturdevant ◽  
Kevin Bock ◽  
Ian Moore ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Genital Tract ◽  
Plasma Cells ◽  
T Cell Response ◽  
Similar Species ◽  
Content Type ◽  
Chlamydia Muridarum

ABSTRACT We studied infection and immunity of hysterectomized mice infected with Chlamydia muridarum and Chlamydia trachomatis to determine if there were differences between these species in their ability to infect vaginal squamous epithelial cells in vivo independently of proximal upper genital tract tissues. We found that C. muridarum readily colonized and infected vaginal squamous epithelial cells, whereas C. trachomatis did not. Primary infection of the vaginal epithelium with C. muridarum produced infections of a duration longer than that reported for normal mice. Infection resulted in an inflammatory response in the vagina characterized by neutrophils and infiltrating submucosal plasma cells consisting primarily of T cells. Despite the delayed clearance, rechallenged C. muridarum-infected mice were highly immune. Mice vaginally infected with C. muridarum produced serum and vaginal wash antibodies and an antigen-specific gamma interferon-dominated Th1-biased T cell response. By comparison, mice vaginally infected with C. trachomatis exhibited transient low-burden infections, produced no detectable tissue inflammatory response, and failed to seroconvert. We discuss how these marked differences in the biology of vaginal infection between these otherwise genetically similar species are possibly linked to pathogen-specific virulence genes and how they may influence pathology and immunity in the upper genital tract.

scholarly journals Gamma Interferon Is Required for Chlamydia Clearance but Is Dispensable for T Cell Homing to the Genital Tract

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Jennifer D. Helble ◽  
Rodrigo J. Gonzalez ◽  
Ulrich H. von Andrian ◽  
Michael N. Starnbach
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Chlamydia Trachomatis ◽  
Genital Tract ◽  
Gamma Interferon ◽  
Cell Homing ◽  
Content Type ◽  
T Cell Homing ◽  
Ifn Γ

ABSTRACT While there is no effective vaccine against Chlamydia trachomatis infection, previous work has demonstrated the importance of C. trachomatis-specific CD4+ T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host’s ability to sense the cytokine gamma interferon (IFN-γ). However, it is unclear what role NR1 production or sensing of IFN-γ plays in T cell homing to the genital tract or T cell-mediated protection against C. trachomatis. Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-γ−/−, and IFN-γR−/− NR1 T cells specifically home to sections in the genital tract that contain C. trachomatis. We also determined that protection against infection requires production of IFN-γ from either NR1 T cells or endogenous cells, further highlighting the importance of IFN-γ in clearing C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is an important mucosal pathogen that is the leading cause of sexually transmitted bacterial infections in the United States. Despite this, there is no vaccine currently available. In order to develop such a vaccine, it is necessary to understand the components of the immune response that can lead to protection against this pathogen. It is well known that antigen-specific CD4+ T cells are critical for Chlamydia clearance, but the contexts in which they are protective or not protective are unknown. Here, we aimed to characterize the importance of gamma interferon production and sensing by T cells and the effects on the immune response to C. trachomatis. Our work here helps to define the contexts in which antigen-specific T cells can be protective, which is critical to our ability to design an effective and protective vaccine against C. trachomatis.

scholarly journals Agglutinating Secretory IgA Preserves Intestinal Epithelial Cell Integrity during Apical Infection by Shigella flexneri

2013 ◽  
Vol 81 (8) ◽  
pp. 3027-3034 ◽  
Author(s):  
Amandine Mathias ◽  
Stéphanie Longet ◽  
Blaise Corthésy
Keyword(s):  
Epithelial Cells ◽  
Tight Junction ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Shigella Flexneri ◽  
Indirect Evidence ◽  
Secretory Iga ◽  
Intestinal Epithelial ◽  
Cell Integrity ◽  
Content Type

ABSTRACTShigella flexneri, by invading intestinal epithelial cells (IECs) and inducing inflammatory responses of the colonic mucosa, causes bacillary dysentery. Although M cells overlying Peyer's patches are commonly considered the primary site of entry ofS. flexneri, indirect evidence suggests that bacteria can also use IECs as a portal of entry to the lamina propria. Passive delivery of secretory IgA (SIgA), the major immunoglobulin secreted at mucosal surfaces, has been shown to protect rabbits from experimental shigellosis, but no information exists as to its molecular role in maintaining luminal epithelial integrity. We have established that the interaction of virulentS. flexneriwith the apical pole of a model intestinal epithelium consisting of polarized Caco-2 cell monolayers resulted in the progressive disruption of the tight junction network and actin depolymerization, eventually resulting in cell death. The lipopolysaccharide (LPS)-specific agglutinating SIgAC5 monoclonal antibody (MAb), but not monomeric IgAC5 or IgGC20 MAbs of the same specificity, achieved protective functions through combined mechanisms, including limitation of the interaction betweenS. flexneriand epithelial cells, maintenance of the tight junction seal, preservation of the cell morphology, reduction of NF-κB nuclear translocation, and inhibition of proinflammatory mediator secretion. Our results add to the understanding of the function of SIgA-mediated immune exclusion by identifying a mode of action whereby the formation of immune complexes translates into maintenance of the integrity of epithelial cells lining the mucosa. This novel mechanism of protection mediated by SIgA is important to extend the arsenal of effective strategies to fight againstS. flexnerimucosal invasion.

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 Chlamydia trachomatis Plasmid Gene Protein 3 Is Essential for the Establishment of Persistent Infection and Associated Immunopathology

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Chunfu Yang ◽  
Laszlo Kari ◽  
Lei Lei ◽  
John H. Carlson ◽  
Li Ma ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Tract Infection ◽  
Antimicrobial Peptides ◽  
Virulence Factor ◽  
Nonhuman Primate ◽  
Persistent Infection ◽  
Genital Tract ◽  
Chlamydial Infection ◽  
Genital Tract Infection ◽  
Content Type

ABSTRACT Chlamydia trachomatis is an obligate intracellular bacterial pathogen that causes blinding trachoma and sexually transmitted disease afflicting hundreds of millions of people globally. A fundamental but poorly understood pathophysiological characteristic of chlamydial infection is the propensity to cause persistent infection that drives damaging inflammatory disease. The chlamydial plasmid is a virulence factor, but its role in the pathogenesis of persistent infection capable of driving immunopathology is unknown. Here, we show by using mouse and nonhuman primate infection models that the secreted plasmid gene protein 3 (Pgp3) is essential for establishing persistent infection. Ppg3-dependent persistent genital tract infection resulted in a severe endometritis caused by an intense infiltration of endometrial submucosal macrophages. Pgp3 released from the cytosol of lysed infected oviduct epithelial cells, not organism outer membrane-associated Pgp3, inhibited the chlamydial killing activity of antimicrobial peptides. Genetic Pgp3 rescue experiments in cathelin-related antimicrobial peptide (CRAMP)-deficient mice showed Pgp3-targeted antimicrobial peptides to subvert innate immunity as a pathogenic strategy to establish persistent infection. These findings provide important advances in understanding the role of Pgp3 in the pathogenesis of persistent chlamydial infection and associated immunopathology. IMPORTANCE Chlamydia trachomatis can cause persistent infection that drives damaging inflammatory responses resulting in infertility and blindness. Little is known about chlamydial genes that cause persistence or factors that drive damaging pathology. In this work, we show that the C. trachomatis plasmid protein gene 3 (Pgp3) is the essential virulence factor for establishing persistent female genital tract infection and provide supportive evidence that Pgp3 functions similarly in a nonhuman primate trachoma model. We further show that persistent Ppg3-dependent infection drives damaging immunopathology. These results are important advances in understanding the pathophysiology of chlamydial persistence.

scholarly journals Anti-Inflammatory Properties of Streptococcus salivarius, a Commensal Bacterium of the Oral Cavity and Digestive Tract

2013 ◽  
Vol 80 (3) ◽  
pp. 928-934 ◽  
Author(s):  
Ghalia Kaci ◽  
Denise Goudercourt ◽  
Véronique Dennin ◽  
Bruno Pot ◽  
Joël Doré ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Oral Cavity ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Streptococcus Salivarius ◽  
Content Type ◽  
Anti Inflammatory

ABSTRACTStreptococcus salivariusis one of the first colonizers of the human oral cavity and gut after birth and therefore may contribute to the establishment of immune homeostasis and regulation of host inflammatory responses. The anti-inflammatory potential ofS. salivariuswas first evaluatedin vitroon human intestinal epithelial cells and human peripheral blood mononuclear cells. We show that liveS. salivariusstrains inhibitedin vitrothe activation of the NF-κB pathway on intestinal epithelial cells. We also demonstrate that the liveS. salivariusJIM8772 strain significantly inhibited inflammation in severe and moderate colitis mouse models. Thesein vitroandin vivoanti-inflammatory properties were not found with heat-killedS. salivarius, suggesting a protective response exclusively with metabolically active bacteria.

scholarly journals Animal Models for Studying Female Genital Tract Infection with Chlamydia trachomatis

2013 ◽  
Vol 81 (9) ◽  
pp. 3060-3067 ◽  
Author(s):  
Evelien De Clercq ◽  
Isabelle Kalmar ◽  
Daisy Vanrompay
Keyword(s):  
Chlamydia Trachomatis ◽  
Animal Models ◽  
Genital Tract ◽  
Transmitted Disease ◽  
Female Genital Tract ◽  
Genital Tract Infection ◽  
Content Type ◽  
Genital Tract Infections ◽  
Tract Infections ◽  
Female Genital

ABSTRACTChlamydia trachomatisis a Gram-negative obligate intracellular bacterial pathogen. It is the leading cause of bacterial sexually transmitted disease in the world, with more than 100 million new cases of genital tract infections withC. trachomatisoccurring each year. Animal models are indispensable for the study ofC. trachomatisinfections and the development and evaluation of candidate vaccines. In this paper, the most commonly used animal models to study female genital tract infections withC. trachomatiswill be reviewed, namely, the mouse, guinea pig, and nonhuman primate models. Additionally, we will focus on the more recently developed pig model.

scholarly journals Inhibition of Indoleamine 2,3-Dioxygenase Activity by Levo-1-Methyl Tryptophan Blocks Gamma Interferon-Induced Chlamydia trachomatis Persistence in Human Epithelial Cells

2011 ◽  
Vol 79 (11) ◽  
pp. 4425-4437 ◽  
Author(s):  
Joyce A. Ibana ◽  
Robert J. Belland ◽  
Arnold H. Zea ◽  
Danny J. Schust ◽  
Takeshi Nagamatsu ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Epithelial Cells ◽  
Gamma Interferon ◽  
Developmental Cycle ◽  
Tryptophan Depletion ◽  
Content Type ◽  
Indoleamine 2,3 Dioxygenase ◽  
Human Epithelial Cells ◽  
Ifn Γ

ABSTRACTGamma interferon (IFN-γ) induces expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1) in human epithelial cells, the permissive cells for the obligate intracellular bacteriumChlamydia trachomatis. IDO1 depletes tryptophan by catabolizing it to kynurenine with consequences forC. trachomatis, which is a tryptophan auxotroph.In vitrostudies reveal that tryptophan depletion can result in the formation of persistent (viable but noncultivable) chlamydial forms. Here, we tested the effects of the IDO1 inhibitor, levo-1-methyl-tryptophan (L-1MT), on IFN-γ-inducedC. trachomatispersistence. We found that addition of 0.2 mM L-1MT to IFN-γ-exposed infected HeLa cell cultures restricted IDO1 activity at the mid-stage (20 h postinfection [hpi]) of the chlamydial developmental cycle. This delayed tryptophan depletion until the late stage (38 hpi) of the cycle. Parallel morphological and gene expression studies indicated a consequence of the delay was a block in the induction ofC. trachomatispersistence by IFN-γ. Furthermore, L-1MT addition allowedC. trachomatisto undergo secondary differentiation, albeit with limited productive multiplication of the bacterium. IFN-γ-induced persistent infections in epithelial cells have been previously reported to be more resistant to doxycycline than normal productive infectionsin vitro. Pertinent to this observation, we found that L-1MT significantly improved the efficacy of doxycycline in clearing persistentC. trachomatisforms. It has been postulated that persistent forms ofC. trachomatismay contribute to chronic chlamydial disease. Our findings suggest that IDO1 inhibitors such as L-1MT might provide a novel means to investigate, and potentially target, persistent chlamydial forms, particularly in conjunction with conventional therapeutics.

scholarly journals TheChlamydia trachomatisPlasmid and CT135 Virulence Factors Are Not Essential for Genital Tract Infection or Pathology in Female Pig-Tailed Macaques

2018 ◽  
Vol 86 (5) ◽  
Author(s):  
Dorothy L. Patton ◽  
Yvonne C. Sweeney ◽  
Audrey E. Baldessari ◽  
Linda Cles ◽  
Laszlo Kari ◽  
...  
Keyword(s):  
Tract Infection ◽  
Virulence Factors ◽  
Genital Tract ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Female Genital Tract ◽  
Wild Type ◽  
Genital Tract Infection ◽  
Content Type ◽  
Cytokine Analysis

ABSTRACTTheChlamydia trachomatisplasmid and inclusion membrane protein CT135 are virulence factors in the pathogenesis of murine female genital tract infection. To determine if these virulence factors play a similar role in female nonhuman primates, we infected pig-tailed macaques with the sameC. trachomatisstrains shown to be important in the murine model. Wild-typeC. trachomatisand its isogenic mutant strain deficient in both plasmid and CT135 were used to infect macaques. Macaques were given primary and repeated cervicovaginal challenges with the wild-type and mutant strains. The infection rate, infection duration, and antibody response were similar among macaques infected with both strains. Unexpectedly, colposcopy, laparoscopy, and histologic analysis revealed no substantial genital tract pathology following either primary or repeated cervicovaginal challenges. Cytokine analysis of cervicovaginal secretions from both challenged groups revealed low concentrations of interleukin 1β (IL-1β) and elevated levels of the interleukin 1 receptor agonist (IL-1RA). We propose that an imbalance of IL-1β and IL-1RA in macaques is the reason for the mild inflammatory responses observed in infected urogenital tissues. Thus, understanding the pathobiology of chlamydial infection requires a better understanding of host epigenetic and chlamydial genetic factors. Our findings also have implications for understanding the high frequency of asymptomatic infections in humans.

scholarly journals Interaction of Chlamydia trachomatis serovar E with male genital tract epithelium results in secretion of proinflammatory cytokines

2007 ◽  
Vol 56 (8) ◽  
pp. 1025-1032 ◽  
Author(s):  
Najwa Al-Mously ◽  
Adrian Eley
Keyword(s):  
Chlamydia Trachomatis ◽  
Epithelial Cells ◽  
Hela Cells ◽  
Genital Tract ◽  
Interleukin 1 ◽  
Female Genital Tract ◽  
Male Genital Tract ◽  
Prostate Epithelial Cells ◽  
Male Genital

Although much has been reported on the in vitro interaction of Chlamydia trachomatis with cells derived from the female genital tract, little is known of its interaction with male genital tract epithelium. The aim of this work was to investigate the effect of C. trachomatis serovar E on immortalized normal human urethral epithelial cells and on immortalized normal adult human prostate epithelial cells with regard to chlamydial growth and secretion of cytokines. After infection, these epithelial cells were assessed for their support of chlamydial growth in comparison with HeLa cells, and cytokine levels in cell culture supernatants were determined by ELISA. Although the male-derived epithelial cells supported growth of chlamydiae, the best growth was seen in HeLa cells. In contrast to prostate epithelial cells, the urethral epithelial cells released much larger quantities of interleukin 1α (IL-1α) following infection, whereas both IL-6 and IL-8 were produced in larger quantities by infected prostate cells. At 7 days post-infection, HeLa cells consistently produced large quantities of all three cytokines. In conclusion, the male-derived cell lines were shown to support the invasion of C. trachomatis and initiate a proinflammatory response to infection. From in vitro studies the suggestion that high levels of IL-6 could be a possible marker for chlamydial prostatitis is confirmed. Although not as marked a change, it is also suggested that higher IL-8 levels could be associated more with infection of the prostate than the urethra. Differential cytokine production by different male-derived epithelial cells could help determine the site of chlamydial infection and help in the study of pathogenesis.

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