scholarly journals Chlamydia muridarum T Cell Antigens and Adjuvants That Induce Protective Immunity in Mice

2012 ◽  
Vol 80 (4) ◽  
pp. 1510-1518 ◽  
Author(s):  
Hong Yu ◽  
Karuna P. Karunakaran ◽  
Xiaozhou Jiang ◽  
Caixia Shen ◽  
Peter Andersen ◽  
...  
Keyword(s):  
T Cell ◽  
Tract Infection ◽  
Genital Tract ◽  
Protective Immunity ◽  
Infection Model ◽  
Genital Tract Infection ◽  
Content Type ◽  
Cell Antigen ◽  
Monophosphoryl Lipid A ◽  
T Cell Antigens

ABSTRACTMajor impediments to aChlamydiavaccine lie in discovering T cell antigens and polarizing adjuvants that stimulate protective immunity. We previously reported the discovery of three T cell antigens (PmpG, PmpF, and RplF) via immunoproteomics that elicited protective immunity in the murine genital tract infection model againstChlamydiainfection after adoptive transfer of antigen-pulsed dendritic cells. To expand the T cell antigen repertoire necessary for aChlamydiavaccine, we evaluated 10 newChlamydiaT cell antigens discovered via immunoproteomics in addition to the 3 antigens reported earlier as a molecular subunit vaccine. We first tested five adjuvants, including three cationic liposome formulations (dimethyldioctadecylammonium bromide-monophosphoryl lipid A [DDA-MPL], DDA-trehalose 6,6′-dibehenate [DDA-TDB {CAF01}], and DDA-monomycolyl glycerol [DDA-MMG {CAF04}]), Montanide ISA720–CpG-ODN1826, and alum using the PmpG protein as a model T cell antigen in the mouse genital tract infection model. The results showed that the cationic liposomal adjuvants DDA-MPL and DDA-TDB elicited the best protective immune responses, characterized by multifunctional CD4+T cells coexpressing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), and reduced infection by more than 3 logs. Using DDA-MPL as an adjuvant, we found that 7 of 13ChlamydiaT cell antigens (PmpG, PmpE, PmpF, Aasf, RplF, TC0420, and TC0825) conferred protection better than or equal to that of the reference vaccine antigen, major outer membrane protein (MOMP). Pools of membrane/secreted proteins, cytoplasmic proteins, and hypothetical proteins were tested individually or in combination. Immunization with combinations protected as well as the best individual protein in that combination. The T cell antigens and adjuvants discovered in this study are of further interest in the development of a molecularly definedChlamydiavaccine.

Gonococcal Adaptation to Palmitic Acid Through farAB Expression and FadD Activity Mutations Increases In Vivo Fitness in a Murine Genital Tract Infection Model

2020 ◽  
Author(s):  
Lingyu Gao ◽  
Zhemin Wang ◽  
Stijn van der Veen
Keyword(s):  
Tract Infection ◽  
Palmitic Acid ◽  
Genital Tract ◽  
Efflux Pump ◽  
Bacterial Pathogen ◽  
Serial Passage ◽  
Infection Model ◽  
Genital Tract Infection ◽  
Long Chain

Abstract Neisseria gonorrhoeae is a bacterial pathogen that colonizes mucosal epithelia that are rich in antimicrobial molecules such as long-chain fatty acids. Here we studied the mechanisms involved in palmitic acid resistance and their impact on in vivo biological fitness in a murine genital tract infection model. A stable palmitic acid-resistant derivative was obtained by serial passage with incremental palmitic acid concentrations. This derivative outcompeted its parent strain for colonization and survival in the murine infection model. Subsequent whole-genome sequencing resulted in the identification of the 3 resistance-related SNPs ihfAC5T, fadDC772T, and farAG-52T (promoter) that were verified for resistance against palmitic acid. Subsequent characterization of the associated resistance determinants showed that ihfAC5T and farAG-52T induced gene expression of the FarAB efflux pump, whereas fadDC772T increased the maximum enzyme activity of the FadD long-chain fatty acid-coenzyme A ligase. Our results highlight the mechanisms involved in gonococcal adaptation to the murine host environment.

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 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 In Situ Analysis of the Evolution of the Primary Immune Response in Murine Chlamydia trachomatis Genital Tract Infection

2000 ◽  
Vol 68 (5) ◽  
pp. 2870-2879 ◽  
Author(s):  
Sandra G. Morrison ◽  
Richard P. Morrison
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chlamydia Trachomatis ◽  
Tract Infection ◽  
Inflammatory Response ◽  
Genital Tract ◽  
Genital Tract Infection ◽  
Tnf Α

ABSTRACT Adaptive immune responses contribute to the resolution ofChlamydia trachomatis genital tract infection and protect against reinfection, but our understanding of the mechanisms of those protective responses is incomplete. In this study, we analyzed by in situ immunohistochemistry the progression of the inflammatory and cytokine responses in the genital tracts of mice vaginally infected with C. trachomatis strain mouse pneumonitis. The cellular inflammatory response was characterized by an initial elevation in myeloid cells in the vagina (day 3) and uterine horns (day 7), followed by a marked rise in the number of T cells, predominantly CD4+ cells. CD8+ T cells and CD45R+B cells were also detected but were much less numerous. Perivascular clusters of CD4+ T cells, which resembled clusters of T cells seen in delayed-type hypersensitivity responses, were evident by 2 weeks postinfection. Following the resolution of infection, few CD8+ T cells and CD45R+ B cells remained, whereas numerous CD4+ T cells and perivascular clusters of CD4+ T cells persisted in genital tract tissues. Interleukin-12 (IL-12)- and tumor necrosis factor alpha (TNF-α)-producing cells were observed in vaginal tissue by day 3 of infection and in uterine tissues by day 7. Cells producing IL-4 or IL-10 were absent from vaginal tissues at day 3 of infection but were present in uterine tissues by day 7 and were consistently more numerous than IL-12- and TNF-α-producing cells. Thus, the evolution of the local inflammatory response was characterized by the accumulation of CD4+ T cells into perivascular clusters and the presence of cells secreting both Th1- and Th2-type cytokines. The persistence of CD4+-T-cell clusters long after infection had resolved (day 70) may provide for a readily mobilizable T-cell response by which previously infected animals can quickly respond to and control a secondary infectious challenge.

scholarly journals NovelChlamydia muridarumT Cell Antigens Induce Protective Immunity against Lung and Genital Tract Infection in Murine Models

2009 ◽  
Vol 182 (3) ◽  
pp. 1602-1608 ◽  
Author(s):  
Hong Yu ◽  
Xiaozhou Jiang ◽  
Caixia Shen ◽  
Karuna P. Karunakaran ◽  
Robert C. Brunham
Keyword(s):  
Tract Infection ◽  
Genital Tract ◽  
Protective Immunity ◽  
Murine Models ◽  
Genital Tract Infection

scholarly journals Chlamydia muridarumGenital and Gastrointestinal Infection Tropism Is Mediated by Distinct Chromosomal Factors

2018 ◽  
Vol 86 (7) ◽  
pp. e00141-18 ◽  
Author(s):  
Sandra G. Morrison ◽  
Amanda M. Giebel ◽  
Evelyn C. Toh ◽  
Horace J. Spencer ◽  
David E. Nelson ◽  
...  
Keyword(s):  
Tract Infection ◽  
Nonsense Mutation ◽  
Genital Tract ◽  
Genital Tract Infection ◽  
Nonsense Mutations ◽  
Content Type ◽  
Infectious Dose ◽  
Chlamydia Muridarum ◽  
Infection Models ◽  
Chromosomal Mutations

ABSTRACTSome members of the genusChlamydia, including the human pathogenChlamydia trachomatis, infect multiple tissues, including the genital and gastrointestinal (GI) tracts. However, it is unknown if bacterial targeting to these sites is mediated by multifunctional or distinct chlamydial factors. We previously showed that disruption of individual large clostridial toxin homologs encoded within theChlamydia muridarumplasticity zone were not critical for murine genital tract infection. Here, we assessed whether cytotoxin genes contribute toC. muridarumGI tropism. Infectivity and shedding of wild-type (WT)C. muridarumand three mutants containing nonsense mutations in different cytotoxin genes,tc0437,tc0438, andtc0439, were compared in mouse genital and GI infection models. One mutant, which had a nonsense mutation intc0439, was highly attenuated for GI infection and had a GI 50% infectious dose (ID50) that was 1,000 times greater than that of the WT. GI inoculation with this mutant failed to elicit anti-chlamydial antibodies or to protect against subsequent genital tract infection. Genome sequencing of thetc0439mutant revealed additional chromosomal mutations, and phenotyping of additional mutants suggested that the GI attenuation might be linked to a nonsense mutation intc0600. The molecular mechanism underlying this dramatic difference in tissue-tropic virulence is not fully understood. However, isolation of these mutants demonstrates that distinct chlamydial chromosomal factors mediate chlamydial tissue tropism and provides a basis for vaccine initiatives to isolate chlamydia strains that are attenuated for genital infection but retain the ability to colonize the GI tract and elicit protective immune responses.

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