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 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 CD4 T Cell Antigens from Staphylococcus aureus Newman Strain Identified following Immunization with Heat-Killed Bacteria

2012 ◽  
Vol 19 (4) ◽  
pp. 477-489 ◽  
Author(s):  
Paulraj K. Lawrence ◽  
Bachra Rokbi ◽  
Nadège Arnaud-Barbe ◽  
Eric L. Sutten ◽  
Junzo Norimine ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
T Cell ◽  
Reverse Genetics ◽  
Vaccine Development ◽  
Protein A ◽  
Cd4 T Cell ◽  
Content Type ◽  
Intramammary Infections ◽  
T Cell Antigens ◽  
Ifn Γ

ABSTRACTStaphylococcus aureusis a commensal bacterium associated with the skin and mucosal surfaces of humans and animals that can also cause chronic infection. The emergence of antibiotic-resistant strains such as methicillin-resistantS. aureus(MRSA) and strains causing chronic intramammary infections (IMI) in cows results in severe human and livestock infections. Conventional approaches to vaccine development have yielded only a few noneffective vaccines against MRSA or IMI strains, so there is a need for improved vaccine development. CD4 T lymphocytes are required for promoting gamma interferon (IFN-γ) mediated immunoglobulin isotype switching in B lymphocytes to produce high-affinity IgG antibodies and IFN-γ-mediated phagocyte activation for an effective resolution of bacterial infection. However, the lack of known CD4 T cell antigens fromS. aureushas made it difficult to design effective vaccines. The goal of this study was to identifyS. aureusproteins recognized by immune CD4 T cells. Using a reverse genetics approach, 43 antigens were selected from theS. aureusNewman strain. These included lipoproteins, proteases, transcription regulators, an alkaline shock protein, conserved-domain proteins, hemolysins, fibrinogen-binding protein, staphylokinase, exotoxin, enterotoxin, sortase, and protein A. Screening of expressed proteins for recall T cell responses in outbred, immune calves identified 13 proteins that share over 80% sequence identity among MRSA or IMI strains. These may be useful for inclusion in a broadly protective multiantigen vaccine against MRSA or IMI.

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 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 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 The Recall Response Induced by Genital Challenge with Chlamydia muridarum Protects the Oviduct from Pathology but Not from Reinfection

2012 ◽  
Vol 80 (6) ◽  
pp. 2194-2203 ◽  
Author(s):  
Melissa M. Riley ◽  
Matthew A. Zurenski ◽  
Lauren C. Frazer ◽  
Catherine M. O'Connell ◽  
Charles W. Andrews ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccine Development ◽  
T Cell Response ◽  
Genital Infection ◽  
Content Type ◽  
Chlamydia Muridarum ◽  
Tube Obstruction ◽  
Fallopian Tube Obstruction ◽  
Tissue Site ◽  
Sterilizing Immunity

ABSTRACTThe significant morbidities of ectopic pregnancy and infertility observed in women afterChlamydia trachomatisgenital infection result from ascension of the bacteria from the endocervix to the oviduct, where an overly aggressive inflammatory response leads to chronic scarring and Fallopian tube obstruction. A vaccine to prevent chlamydia-induced disease is urgently needed. An important question for vaccine development is whether sterilizing immunity at the level of the oviduct is essential for protection because of the possibility that a chlamydial component drives a deleterious anamnestic T cell response upon oviduct reinfection. We show that mice inoculated with attenuated plasmid-cured strains ofChlamydia muridarumare protected from oviduct pathology upon challenge with wild-typeC. muridarumNigg despite induction of a response that did not prevent reinfection of the oviduct. Interestingly, repeated abbreviated infections with Nigg also elicited recall responses that protected the oviduct from pathology despite low-level reinfection of this vulnerable tissue site. Challenged mice displayed significant decreases in tissue infiltration of inflammatory leukocytes with marked reductions in frequencies of neutrophils but significant increases in frequencies of CD4 Th1 and CD8 T cells. An anamnestic antibody response was also detected. These data indicate that exposure to a live attenuated chlamydial vaccine or repeated abbreviated genital infection with virulent chlamydiae promotes anamnestic antibody and T cell responses that protect the oviduct from pathology despite a lack of sterilizing immunity at the site.

scholarly journals Trypanosoma cruzitrans-Sialidase Prevents Elicitation of Th1 Cell Response via Interleukin 10 and Downregulates Th1 Effector Cells

2015 ◽  
Vol 83 (5) ◽  
pp. 2099-2108 ◽  
Author(s):  
Pablo Ruiz Díaz ◽  
Juan Mucci ◽  
María Ana Meira ◽  
Yanina Bogliotti ◽  
Daniel Musikant ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Neutralizing Antibodies ◽  
Cd4 T Cell ◽  
Th1 Cell ◽  
Content Type ◽  
Th1 Response ◽  
Ifn Γ ◽  
Antigen Presenting

Thetrans-sialidases (TSs) fromTrypanosoma cruzi, the agent of Chagas disease, are virulence factors shed to the bloodstream that induce strong alterations in the immune system. Here, we report that both enzymatically active TS (aTS) and its lectinlike isoform (iTS) disturb CD4 T cell physiology, inducing downregulation of Th1 cell functionality andin vivocell expansion. By using ovalbumin-specific DO11.10 cells as tracers of clones developing the Th1 phenotype, we found that the infection induced significant amounts of gamma interferon (IFN-γ) but low levels of interleukin 2 (IL-2) and increased IL-4 productionin vivo, in agreement with a mixed T helper response. The production of cytokines associated with the Th2 phenotype was prevented by passive transfer of anti-TS neutralizing antibodies. TSs also reduced the T cell receptor signaling as assayed by Zap-70 phosphorylation. TSs also reduced IL-2 and IFN-γ secretion, with a concomitant increase in IL-4 production and then an unbalancing of the CD4 T cell response toward the Th2 phenotype. This effect was prevented by using anti-IL-10 neutralizing antibodies or IL-10−/−antigen-presenting cells, supporting the subversion of this regulatory pathway. In support, TSs stimulated IL-10 secretion by antigen-presenting cells during their interaction with CD4 T cells. When polarized cells were stimulated in the presence of TSs, the secretion of IL-2 and IFN-γ was strongly downregulated in Th1 cells, while IL-2 production was upregulated in Th2 cells. Although the Th1 response is associated with host survival, it may simultaneously induce extensive damage to infected tissues. Thus, by delaying the elicitation of the Th1 response and limiting its effector properties, TSs restrain the cell response, supportingT. cruzicolonization and persistence while favoring host survival.

scholarly journals B Cell Presentation of Chlamydia Antigen Selects Out Protective CD4γ13 T Cells: Implications for Genital Tract Tissue-Resident Memory Lymphocyte Clusters

2017 ◽  
Vol 86 (2) ◽  
Author(s):  
Raymond M. Johnson ◽  
Hong Yu ◽  
Norma Olivares Strank ◽  
Karuna Karunakaran ◽  
Ying Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Genital Tract ◽  
Cell Subset ◽  
Cd4 T Cell ◽  
Content Type ◽  
T Cell Subset ◽  
Ifn Γ

ABSTRACTSurveillance and defense of the enormous mucosal interface with the nonsterile world are critical to protecting the host from a wide range of pathogens.Chlamydia trachomatisis an intracellular bacterial pathogen that replicates almost exclusively in the epithelium of the reproductive tract. The fallopian tubes and vagina are poorly suited to surveillance and defense, with limited immune infrastructure positioned near the epithelium. However, a dynamic process during clearing primary infections leaves behind new lymphoid clusters immediately beneath the epithelium. These memory lymphocyte clusters (MLCs) harboring tissue-resident memory (Trm) T cells are presumed to play an important role in protection from subsequent infections. Histologically, humanChlamydiaMLCs have prominent B cell populations. We investigated the status of genital tract B cells duringC. muridaruminfections and the nature of T cells recovered from immune mice using immune B cells as antigen-presenting cells (APCs). These studies revealed a genital tract plasma B cell population and a novel genital tract CD4 T cell subset producing both gamma interferon (IFN-γ) and interleukin-13 (IL-13). A panel of CD4 T cell clones and microarray analysis showed that the molecular fingerprint of CD4γ13 T cells includes a Trm-like transcriptome. Adoptive transfer of aChlamydia-specific CD4γ13 T cell clone completely prevented oviduct immunopathology without accelerating bacterial clearance. Existence of a CD4γ13 T cell subset provides a plausible explanation for the observation that human peripheral blood mononuclear cell (PBMC)Chlamydia-specific IFN-γ and IL-13 responses predict resistance to reinfection.

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