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.

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 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 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 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 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 The Plasmid-Encoded pGP3 PromotesChlamydiaEvasion of Acidic Barriers in Both Stomach and Vagina

2019 ◽  
Vol 87 (5) ◽  
Author(s):  
Tianyuan Zhang ◽  
Zhi Huo ◽  
Jingyue Ma ◽  
Cheng He ◽  
Guangming Zhong
Keyword(s):  
Lactic Acid ◽  
Gastrointestinal Tract ◽  
Genital Tract ◽  
Sexual Transmission ◽  
Content Type ◽  
Chlamydia Muridarum ◽  
Lower Genital Tract ◽  
Colonization Ability ◽  
Gastric Barrier

ABSTRACTAlthoughChlamydia trachomatisis a human genital tract pathogen, chlamydial organisms have frequently been detected in both vaginal and rectal swab samples of animals and humans. The plasmid-encoded pGP3, a genital tract virulence factor, is essential forChlamydia muridarumto colonize the mouse gastrointestinal tract. However, intracolon inoculation to bypass the gastric barrier rescued the colonization ability of a pGP3-deficientC. muridarummutant, suggesting that pGP3 is required forC. muridarumto reach but not to colonize the large intestine. The pGP3-deficient mutant was rapidly cleared in the stomach and was 100-fold more susceptible to gastric killing. In mice genetically deficient in gastrin, a key regulator for gastric acid production, or pharmacologically treated with a proton pump inhibitor, the ability of pGP3-deficientC. muridarumto colonize the gastrointestinal tract was rescued. The pGP3-dependent resistance was further recapitulatedin vitrowith treatments with HCl, pepsin, or sarkosyl. In the genital tract, deficiency in pGP3 significantly reducedC. muridarumsurvival in the mouse vagina and increasedC. muridarumsusceptibility to vaginal killing by ∼8 times. The pGP3-deficientC. muridarumwas more susceptible to lactic acid killing, and the pGP3 deficiency also significantly increasedC. trachomatissusceptibility to lactic acid. The above-described observations together suggest thatChlamydiamay have acquired the plasmid-encoded pGP3 to overcome the gastric barrier during its adaptation to the gastrointestinal tract and the pGP3-dependent resistance may enable chlamydial evasion of the female lower genital tract barrier during sexual transmission.

scholarly journals The Chlamydia muridarum Organisms Fail to Auto-Inoculate the Mouse Genital Tract after Colonization in the Gastrointestinal Tract for 70 days

PLoS ONE ◽  
2016 ◽  
Vol 11 (5) ◽  
pp. e0155880 ◽  
Author(s):  
Luying Wang ◽  
Qi Zhang ◽  
Tianyuan Zhang ◽  
Yuyang Zhang ◽  
Cuiming Zhu ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Genital Tract ◽  
Chlamydia Muridarum

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.

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 Lipid A’s Structure Mediates Neisseria gonorrhoeae Fitness during Experimental Infection of Mice and Men

mBio ◽  
2013 ◽  
Vol 4 (6) ◽  
Author(s):  
Marcia M. Hobbs ◽  
James E. Anderson ◽  
Jacqueline T. Balthazar ◽  
Justin L. Kandler ◽  
Russell W. Carlson ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Genital Tract ◽  
Lipid A ◽  
Female Genital Tract ◽  
Treatment Strategies ◽  
Wild Type ◽  
Genital Tract Infection ◽  
Content Type

ABSTRACT Phosphoethanolamine (PEA) on Neisseria gonorrhoeae lipid A influences gonococcal inflammatory signaling and susceptibility to innate host defenses in in vitro models. Here, we evaluated the role of PEA-decorated gonococcal lipid A in competitive infections in female mice and in male volunteers. We inoculated mice and men with mixtures of wild-type N. gonorrhoeae and an isogenic mutant that lacks the PEA transferase, LptA. LptA production conferred a marked survival advantage for wild-type gonococci in the murine female genital tract and in the human male urethra. Our studies translate results from test tube to animal model and into the human host and demonstrate the utility of the mouse model for studies of virulence factors of the human-specific pathogen N. gonorrhoeae that interact with non-host-restricted elements of innate immunity. These results validate the use of gonococcal LptA as a potential target for development of novel immunoprophylactic strategies or antimicrobial treatments. IMPORTANCE Gonorrhea is one of the most common bacterial sexually transmitted infections, and increasing antibiotic resistance threatens the use of currently available antimicrobial therapies. In this work, encompassing in vitro studies and in vivo studies of animal and human models of experimental genital tract infection, we document the importance of lipid A’s structure, mediated by a single bacterial enzyme, LptA, in enhancing the fitness of Neisseria gonorrhoeae. The results of these studies suggest that novel agents targeting LptA may offer urgently needed prevention or treatment strategies for gonorrhea.

Sign in / Sign up

Export Citation Format

Share Document