scholarly journals The Genital Tract Virulence Factor pGP3 Is Essential for Chlamydia muridarum Colonization in the Gastrointestinal Tract

2017 ◽  
Vol 86 (1) ◽  
Author(s):  
Lili Shao ◽  
Tianyuan Zhang ◽  
Jose Melero ◽  
Yumeng Huang ◽  
Yuanjun Liu ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Virulence Factor ◽  
Genital Tract ◽  
Gi Tract ◽  
Content Dissemination ◽  
Content Type ◽  
Chlamydia Muridarum ◽  
Colonization Factor ◽  
Genital Tract Infections ◽  
Tract Infections

ABSTRACTThe cryptic plasmid is essential forChlamydia muridarumdissemination from the genital tract to the gastrointestinal (GI) tract. Following intravaginal inoculation, aC. muridarumstrain deficient in plasmid-encoded pGP3 or pGP4 but not pGP5, pGP7, or pGP8 failed to spread to the mouse gastrointestinal tract, although mice infected with these strains developed productive genital tract infections. pGP3- or pGP4-deficient strains also failed to colonize the gastrointestinal tract when delivered intragastrically. pGP4 regulates pGP3, while pGP3 does not affect pGP4 expression, indicating that pGP3 is critical forC. muridarumcolonization of the gastrointestinal tract. Mutants deficient in GlgA, a chromosome-encoded protein regulated by pGP4, also consistently colonized the mouse gastrointestinal tract. Interestingly,C. muridarumcolonization of the gastrointestinal tract positively correlated with pathogenicity in the upper genital tract. pGP3-deficientC. muridarumstrains did not induce hydrosalpinx or spread to the GI tract even when delivered to the oviduct by intrabursal inoculation. Thus, the current study not only has revealed that pGP3 is a novel chlamydial colonization factor in the gastrointestinal tract but also has laid a foundation for investigating the significance of gastrointestinalChlamydia.

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 PmpG303-311, a Protective Vaccine Epitope That Elicits Persistent Cellular Immune Responses in Chlamydia muridarum-Immune Mice

2012 ◽  
Vol 80 (6) ◽  
pp. 2204-2211 ◽  
Author(s):  
Raymond M. Johnson ◽  
Hong Yu ◽  
Micah S. Kerr ◽  
James E. Slaven ◽  
Karuna P. Karunakaran ◽  
...  
Keyword(s):  
T Cell ◽  
Genital Tract ◽  
Vaccine Development ◽  
Cd4 T Cell ◽  
Unique Challenge ◽  
Content Type ◽  
Chlamydia Muridarum ◽  
Genital Tract Infections ◽  
Tract Infections ◽  
Antigen Presenting

ABSTRACTUrogenitalChlamydiaserovars replicating in reproductive epithelium pose a unique challenge to host immunity and vaccine development. Previous studies have shown that CD4 T cells are necessary and sufficient to clear primaryChlamydia muridarumgenital tract infections in the mouse model, making a protective CD4 T cell response a logical endpoint for vaccine development. Our previous proteomics studies identified 13 candidateChlamydiaproteins for subunit vaccines. Of those, PmpG-1 is the most promising vaccine candidate. To further that work, we derived a PmpG303-311-specific multifunctional Th1 T cell clone, designated PmpG1.1, from an immune C57BL/6 mouse and used it to investigate the presentation of the PmpG303-311epitope by infected epithelial cells. Epithelial presentation of the PmpG303-311epitope required bacterial replication, occurred 15 to 18 h postinfection, and was unaffected by gamma interferon (IFN-γ) pretreatment. Unlike epitopes recognized by otherChlamydia-specific CD4 T cell clones, the PmpG303-311epitope persisted on splenic antigen-presenting cells (APC) of mice that cleared primary genital tract infections. PmpG1.1 was activated by unmanipulated irradiated splenocytes from immune mice without addition of exogenousChlamydiaantigen, and remarkably, activation of PmpG1.1 by unmanipulated immune splenocytes was stronger 6 months postinfection than it was 3 weeks postinfection. Enhanced presentation of PmpG303-311epitope on splenic APC 6 months postinfection reflects some type of “consolidation” of a protective immune response. Understanding the antigen-presenting cell populations responsible for presenting PmpG303-311early (3 weeks) and late (6 months) postinfection will likely provide important insights into stable protective immunity againstChlamydiainfections of the genital tract.

scholarly journals Mutational Analysis of the Chlamydia muridarum Plasticity Zone

2015 ◽  
Vol 83 (7) ◽  
pp. 2870-2881 ◽  
Author(s):  
Krithika Rajaram ◽  
Amanda M. Giebel ◽  
Evelyn Toh ◽  
Shuai Hu ◽  
Jasmine H. Newman ◽  
...  
Keyword(s):  
Cell Culture ◽  
Genital Tract ◽  
Mutational Analysis ◽  
Genomic Diversity ◽  
Infection Model ◽  
Plasticity Zone ◽  
Content Type ◽  
Chlamydia Muridarum ◽  
Ifn Γ ◽  
Tract Infections

Pathogenically diverseChlamydiaspp. can have surprisingly similar genomes.Chlamydia trachomatisisolates that cause trachoma, sexually transmitted genital tract infections (chlamydia), and invasive lymphogranuloma venereum (LGV) and the murine strainChlamydia muridarumshare 99% of their gene content. A region of high genomic diversity betweenChlamydiaspp. termed the plasticity zone (PZ) may encode niche-specific virulence determinants that dictate pathogenic diversity. We hypothesized that PZ genes might mediate the greater virulence and gamma interferon (IFN-γ) resistance ofC. muridarumcompared toC. trachomatisin the murine genital tract. To test this hypothesis, we isolated and characterized a series ofC. muridarumPZ nonsense mutants. Strains with nonsense mutations in chlamydial cytotoxins,guaBA-add, and a phospholipase D homolog developed normally in cell culture. Two of the cytotoxin mutants were less cytotoxic than the wild type, suggesting that the cytotoxins may be functional. However, none of the PZ nonsense mutants exhibited increased IFN-γ sensitivity in cell culture or were profoundly attenuated in a murine genital tract infection model. Our results suggest thatC. muridarumPZ genes are transcribed—and some may produce functional proteins—but are dispensable for infection of the murine genital tract.

scholarly journals The Contribution of Cervicovaginal Infections to the Immunomodulatory Effects of Hormonal Contraception

mBio ◽  
2015 ◽  
Vol 6 (5) ◽  
Author(s):  
Raina N. Fichorova ◽  
Pai-Lien Chen ◽  
Charles S. Morrison ◽  
Gustavo F. Doncel ◽  
Kevin Mendonca ◽  
...  
Keyword(s):  
Hiv Risk ◽  
Genital Tract ◽  
Molecular Mechanisms ◽  
Reproductive Age ◽  
Hormonal Contraceptives ◽  
Enzyme Linked Immunosorbent Assay ◽  
Nugent Score ◽  
Content Type ◽  
Genital Tract Infections ◽  
Tract Infections

ABSTRACT Particular types of hormonal contraceptives (HCs) and genital tract infections have been independently associated with risk of HIV-1 acquisition. We examined whether immunity in women using injectable depot medroxyprogesterone acetate (DMPA), combined oral contraceptives (COC), or no HCs differs by the presence of cervicovaginal infections. Immune mediators were quantified in cervical swabs from 832 HIV-uninfected reproductive-age Ugandans and Zimbabweans. Bacterial infections and HIV were diagnosed by PCR, genital herpes serostatus by enzyme-linked immunosorbent assay (ELISA), altered microflora by Nugent score, and Trichomonas vaginalis and Candida albicans infection by wet mount. Generalized linear models utilizing Box-Cox-Power transformation examined associations between levels of mediators, infection status, and HCs. In no-HC users, T. vaginalis was associated with broadest spectrum of aberrant immunity (higher interleukin 1β [IL-1β], IL-8, macrophage inflammatory protein 3α [MIP-3α], β-defensin 2 [BD2], and IL-1 receptor antigen [IL-1RA]). In women with a normal Nugent score and no genital infection, compared to the no-HC group, COC users showed higher levels of IL-1β, IL-6, IL-8, and IL-1RA, while DMPA users showed higher levels of RANTES and lower levels of BD2, both associated with HIV seroconversion. These effects of COC were blunted in the presence of gonorrhea, chlamydia, trichomoniasis, candidiasis, and an abnormal Nugent score; however, RANTES was increased among COC users with herpes, chlamydia, and abnormal Nugent scores. The effect of DMPA was exacerbated by lower levels of IL-1RA in gonorrhea, chlamydia, or herpes, SLPI in gonorrhea, and IL-1β, MIP-3α, and IL-1RA/IL1β ratio in trichomoniasis. Thus, the effects of HC on cervical immunity depend on the genital tract microenvironment, and a weakened mucosal barrier against HIV may be a combined resultant of genital tract infections and HC use. IMPORTANCE In this article, we show that in young reproductive-age women most vulnerable to HIV, hormonal contraceptives are associated with altered cervical immunity in a manner dependent on the presence of genital tract infections. Through altered immunity, hormones may predispose women to bacterial and viral pathogens; conversely, a preexisting specific infection or disturbed vaginal microbiota may suppress the immune activation by levonorgestrel or exacerbate the suppressed immunity by DMPA, thus increasing HIV risk by their cumulative action. Clinical studies assessing the effects of contraception on HIV susceptibility and mucosal immunity may generate disparate results in populations that differ by microbiota background or prevalence of undiagnosed genital tract infections. A high prevalence of asymptomatic infections among HC users that remain undiagnosed and untreated raises even more concerns in light of their combined effects on biomarkers of HIV risk. The molecular mechanisms of the vaginal microbiome's simultaneous interactions with hormones and HIV remain to be elucidated.

scholarly journals Intravenous Inoculation with Chlamydia muridarum Leads to a Long-Lasting Infection Restricted to the Gastrointestinal Tract

2016 ◽  
Vol 84 (8) ◽  
pp. 2382-2388 ◽  
Author(s):  
Jin Dai ◽  
Tianyuan Zhang ◽  
Luying Wang ◽  
Lili Shao ◽  
Cuiming Zhu ◽  
...  
Keyword(s):  
Sexual Behavior ◽  
Gastrointestinal Tract ◽  
Mouse Strain ◽  
Genital Tract ◽  
Ex Vivo ◽  
Circulatory System ◽  
Content Type ◽  
Chlamydia Muridarum ◽  
Initial Stage ◽  
Intravenous Inoculation

Chlamydiahas been detected in the gastrointestinal tracts of both animals and humans. However, it remains unclear whether the chlamydial organisms can be introduced into the gastrointestinal tract via pathways independent of the oral and anal routes. We have recently shown thatChlamydia muridarumspreads from the genital tract to the gastrointestinal tract potentially via the circulatory system. To test whether hematogenousC. muridarumcan spread to and establish a long-lasting colonization in the mouse gastrointestinal tract, we inoculated mice intravenously with a luciferase-expressingC. muridarumstrain and monitored its distribution. After tail vein inoculation, most luciferase-generated bioluminescence signals were detected in the mouse abdominal area throughout the experiment. Theex vivoimaging revealed that the abdominal signals came from the gastrointestinal tract tissues. Simultaneous monitoring of chlamydial organisms in individual organs or tissues revealed an initial stage of systemic spreading followed by a long-lasting infection in the gastrointestinal tract. A retro-orbital vein inoculation of theC. muridarumorganisms at a lower dose in a different mouse strain also led to colonization of the gastrointestinal tract. We have demonstrated that intravenousC. muridaruminoculation can result in colonization of the gastrointestinal tract, suggesting that the chlamydial organisms may use the sexual behavior-independent circulation pathway to infect the gastrointestinal tract.

scholarly journals Identifying a Role for Toll-Like Receptor 3 in the Innate Immune Response to Chlamydia muridarum Infection in Murine Oviduct Epithelial Cells

2011 ◽  
Vol 80 (1) ◽  
pp. 254-265 ◽  
Author(s):  
Wilbert A. Derbigny ◽  
LaTasha R. Shobe ◽  
Jasmine C. Kamran ◽  
Katherine S. Toomey ◽  
Susan Ofner
Keyword(s):  
Epithelial Cells ◽  
Toll Like Receptor ◽  
Content Type ◽  
Immune Modulators ◽  
Chlamydia Muridarum ◽  
Major Cell Type ◽  
Genital Tract Infections ◽  
Inflammatory Cytokine Response ◽  
Tract Infections ◽  
Cell Data

ABSTRACTBecause epithelial cells are the major cell type productively infected withChlamydiaduring genital tract infections, the overall goal of our research was to understand the contribution of infected epithelial cells to the host defense. We previously showed that Toll-like receptor 3 (TLR3) is the critical pattern recognition receptor in oviduct epithelial (OE) cells that is stimulated duringChlamydiainfection, resulting in the synthesis of beta interferon (IFN-β). Here, we present data that implicates TLR3 in the expression of a multitude of other innate-inflammatory immune modulators including interleukin-6 (IL-6), CXCL10, CXCL16, and CCL5. We demonstrate thatChlamydia-induced expression of these cytokines is severely disrupted in TLR3-deficient OE cells, whereasChlamydiareplication in the TLR3-deficient cells is more efficient than in wild-type OE cells. Pretreatment of the TLR3-deficient OE cells with 50 U of IFN-β/ml prior to infection diminishedChlamydiareplication and restored the ability ofChlamydiainfection to induce IL-6, CXCL10, and CCL5 expression in TLR3-deficient OE cells; however, CXCL16 induction was not restored by IFN-β preincubation. Our findings were corroborated in pathway-focused PCR arrays, which demonstrated a multitude of different inflammatory genes that were defectively regulated duringChlamydiainfection of the TLR3-deficient OE cells, and we found that some of these genes were induced only when IFN-β was added prior to infection. Our OE cell data implicate TLR3 as an essential inducer of IFN-β and other inflammatory mediators by epithelial cells duringChlamydiainfection and highlight the contribution of TLR3 to the inflammatory cytokine response.

scholarly journals Distinct Roles of Chromosome- versus Plasmid-Encoded Genital Tract Virulence Factors in PromotingChlamydia muridarumColonization in the Gastrointestinal Tract

2019 ◽  
Vol 87 (8) ◽  
Author(s):  
John J. Koprivsek ◽  
Tianyuan Zhang ◽  
Qi Tian ◽  
Ying He ◽  
Hong Xu ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Virulence Factors ◽  
Genital Tract ◽  
Oral Delivery ◽  
Content Type ◽  
Chlamydia Muridarum ◽  
Ifn Γ ◽  
Plasmid Mutant ◽  
Increased Susceptibility ◽  
Do So

ABSTRACTThe genital pathogenChlamydiais known to colonize the gastrointestinal tract. Orally deliveredChlamydia muridarumcan reach the colon and maintain a long-lasting colonization there. However,C. muridarumwith mutations in chromosomal genestc0237andtc0668(designated a chromosomal mutant) or deficient in plasmid-encoded pGP3 (designated a plasmid mutant) is unable to do so. We now report that the chromosomal mutant is still able to reach the colon while the plasmid mutant fails to do so following an oral delivery, suggesting that lack of colon colonization by different mutants may involve distinct mechanisms. Consistently, a direct intracolonic delivery selectively restored the ability of the plasmid mutant, but not the chromosomal mutant, to colonize the colon. The chromosomal mutant was rescued only in the colon of mice deficient in gamma interferon (IFN-γ). Thus, the chromosomal mutant’s deficiency in colonizing colonic mucosal tissue is likely due to its increased susceptibility to IFN-γ-mediated immunity. Furthermore, IFN-γ deficiency was sufficient for rescuing colon colonization of an orally delivered chromosomal mutant but not plasmid mutant while mice deficient in gastric acid production rescued the plasmid mutant but not the chromosomal mutant. Both mutants are attenuated in inducing genital tract pathology. Thus, we propose that chlamydial chromosomal-gene-encoded genital tract virulence factors may be essential forChlamydiato maintain long-lasting colonization in the colon while the plasmid may enableChlamydiato reach the colon by promoting evasion of gastric barriers.

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 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 In VivoandEx VivoImaging Reveals a Long-Lasting Chlamydial Infection in the Mouse Gastrointestinal Tract following Genital Tract Inoculation

2015 ◽  
Vol 83 (9) ◽  
pp. 3568-3577 ◽  
Author(s):  
Qi Zhang ◽  
Yumeng Huang ◽  
Siqi Gong ◽  
Zhangsheng Yang ◽  
Xin Sun ◽  
...  
Keyword(s):  
Genital Tract ◽  
Chlamydial Infection ◽  
Ex Vivo ◽  
Mouse Strains ◽  
Gi Tract ◽  
Tubal Infertility ◽  
Content Type ◽  
Chlamydia Muridarum ◽  
Rapid Ascent

Intravaginal infection withChlamydia muridarumin mice can ascend to the upper genital tract, resulting in hydrosalpinx, a pathological hallmark for tubal infertility in women infected withC. trachomatis. Here, we utilizedin vivoimaging ofC. muridaruminfection in mice following an intravaginal inoculation and confirmed the rapid ascent of the chlamydial organisms from the lower to upper genital tracts. Unexpectedly, theC. muridarum-derived signal was still detectable in the abdominal area 100 days after inoculation.Ex vivoimaging of the mouse organs revealed that the long-lasting presence of the chlamydial signal was restricted to the gastrointestinal (GI) tract, which was validated by directly measuring the chlamydial live organisms and genomes in the same organs. TheC. muridarumorganisms spreading from the genital to the GI tracts were detected in different mouse strains and appeared to be independent of oral or rectal routes. Mice prevented from orally taking up excretions also developed the long-lasting GI tract infection. Inoculation ofC. muridarumdirectly into the upper genital tract, which resulted in a delayed vaginal shedding of live organisms, accelerated the chlamydial spreading to the GI tract. Thus, we have demonstrated that the genital tract chlamydial organisms may use a systemic route to spread to and establish a long-lasting infection in the GI tract. The significance of the chlamydial spreading from the genital to GI tracts is discussed.

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