scholarly journals Growth of Neisseria gonorrhoeae in the Female Mouse Genital Tract Does Not Require the Gonococcal Transferrin or Hemoglobin Receptors and May Be Enhanced by Commensal Lactobacilli

2002 ◽  
Vol 70 (5) ◽  
pp. 2549-2558 ◽  
Author(s):  
Ann E. Jerse ◽  
Emily T. Crow ◽  
Amy N. Bordner ◽  
Ishrat Rahman ◽  
Cynthia Nau Cornelissen ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Iron Chelator ◽  
Iron Store ◽  
Human Transferrin ◽  
Mucosal Surfaces ◽  
Phase Variants

ABSTRACT Neisseria gonorrhoeae is capable of utilizing a variety of iron sources in vitro, including human transferrin, human lactoferrin, hemoglobin, hemoglobin-haptoglobin complexes, heme, and heterologous siderophores. Transferrin has been implicated as a critical iron store for N. gonorrhoeae in the human male urethra. The demonstration that gonococci can infect the lower genital tracts of estradiol-treated BALB/c mice in the absence of human transferrin, however, suggests that other usable iron sources are present in the murine genital tract. Here we demonstrate that gonococcal transferrin and hemoglobin receptor mutants are not attenuated in mice, thereby ruling out transferrin and hemoglobin as essential for murine infection. An increased frequency of phase variants with the hemoglobin receptor “on” (Hg+) occurred in ca. 50% of infected mice; this increase was temporally associated with an influx of neutrophils and detectable levels of hemoglobin in the vagina, suggesting that the presence of hemoglobin in inflammatory exudates selects for Hg+ phase variants during infection. We also demonstrate that commensal lactobacilli support the growth of N. gonorrhoeae in vitro unless an iron chelator is added to the medium. We hypothesize that commensal lactobacilli may enhance growth of gonococci in vivo by promoting the solubilization of iron on mucosal surfaces through the production of metabolic intermediates. Finally, transferrin-binding lipoprotein (TbpB) was detected on gonococci in vaginal smears, suggesting that although gonococci replicate within the genital tracts of mice, they may be sufficiently iron-stressed to express iron-repressible proteins. In summary, these studies support the potential role of nontransferrin, nonhemoglobin iron sources during gonococcal infection of the female 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.

scholarly journals α-2,3-Sialyltransferase Enhances Neisseria gonorrhoeae Survival during Experimental Murine Genital Tract Infection

2006 ◽  
Vol 74 (7) ◽  
pp. 4094-4103 ◽  
Author(s):  
Hong Wu ◽  
Ann E. Jerse
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Genital Tract ◽  
In Vitro Assays ◽  
In Vivo Model ◽  
Wild Type ◽  
Genital Tract Infection ◽  
Direct Demonstration ◽  
Increased Sensitivity

ABSTRACT The addition of host-derived sialic acid to Neisseria gonorrhoeae lipooligosaccharide is hypothesized to be an important mechanism by which gonococci evade host innate defenses. This hypothesis is based primarily on in vitro assays of complement-mediated and phagocytic killing. Here we report that a nonpolar α-2,3-sialyltransferase (lst) mutant of N. gonorrhoeae was significantly attenuated in its capacity to colonize the lower genital tract of 17-β estradiol-treated female BALB/c mice during competitive infection with the wild-type strain. Genetic complementation of the lst mutation restored recovery of the mutant to wild-type levels. Studies with B10.D2-HCoH2dH2-T18c/OSN (C5-deficient) mice showed that attenuation of the lst mutant was not due to increased sensitivity to complement-mediated bacteriolysis, a result that is consistent with recently reported host restrictions in the complement cascade. However, Lst-deficient gonococci were killed more rapidly than sialylated wild-type gonococci following intraperitoneal injection into normal mice, which is consistent with sialylation conferring protection against killing by polymorphonuclear leukocytes (PMNs). As reported for human PMNs, sialylated gonococci were more resistant to killing by murine PMNs, and sialylation led to reduced association with and induction of a weaker respiratory burst in PMNs from estradiol-treated mice. In summary, these studies suggest sialylation confers a survival advantage to N. gonorrhoeae in mice by increasing resistance to PMN killing. This report is the first direct demonstration that α-2,3-sialyltransferase contributes to N. gonorrhoeae pathogenesis in an in vivo model. This study also validates the use of experimental murine infection to study certain aspects of gonococcal pathogenesis.

scholarly journals Immune Pathogenesis of Asymptomatic Chlamydia trachomatis Infections in the Female Genital Tract

1995 ◽  
Vol 3 (4) ◽  
pp. 169-174 ◽  
Author(s):  
Steven S. Witkin
Keyword(s):  
Chlamydia Trachomatis ◽  
Genital Tract ◽  
Pregnancy Loss ◽  
Early Stage ◽  
Female Genital Tract ◽  
In Vivo Studies ◽  
Fallopian Tubes ◽  
Female Genital

Chlamydia trachomatis (CT) infections of the female genital tract, although frequently asymptomatic, are a major cause of fallopian-tube occlusion and infertility. Early stage pregnancy loss may also be due to an unsuspected and undetected CT infection. In vitro and in vivo studies have demonstrated that this organism can persist in the female genital tract in a form undetectable by culture. The mechanism of tubal damage as well as the rejection of an embryo may involve an initial immune sensitization to the CT 60 kD heat shock protein (HSP), followed by a reactivation of HSP-sensitized lymphocytes in response to the human HSP and the subsequent release of inflammatory cytokines. The periodic induction of human HSP expression by various microorganisms or by noninfectious mechanisms in the fallopian tubes of women sensitized to the CT HSP may eventually result in tubal scarring and occlusion. Similarly, an immune response to human HSP expression during the early stages of pregnancy may interfere with the immune regulatory mechanisms required for the maintenance of a semiallogeneic embryo.

scholarly journals Sperm migration in the genital tract - in silico experiments identify key factors for reproductive success

2020 ◽  
Author(s):  
Jorin Diemer ◽  
Jens Hahn ◽  
Björn Goldenbogen ◽  
Karin Müller ◽  
Edda Klipp
Keyword(s):  
Reproductive Success ◽  
In Silico ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Male Gametes ◽  
Sperm Migration ◽  
Sperm Motion ◽  
Female Genital

Sperm migration in the female genital tract controls sperm selection and, therefore, reproductive success as male gametes are conditioned for fertilization while their number is dramatically reduced. Mechanisms underlying sperm migration are mostly unknown, since in vivo investigations are mostly unfeasible for ethical or practical reasons. By presenting a spatio-temporal model of the mammalian female genital tract combined with agent-based description of sperm motion and interaction as well as parameterizing it with bovine data, we offer an alternative possibility for studying sperm migration in silico. The model incorporates genital tract geometry as well as biophysical principles of sperm motion observed in vitro such as positive rheotaxis and thigmotaxis. This model for sperm migration from vagina to oviducts was successfully tested against in vivo data from literature. We found that physical sperm characteristics such as velocity and directional stability as well as sperm-fluid interactions and wall alignment are critical for success, i.e. sperms reaching the oviducts. Therefore, we propose that these identified sperm parameters should be considered in detail for conditioning sperm in artificial selection procedures since the natural processes are normally bypassed in reproductive in vitro technologies. The tremendous impact of mucus flow to support sperm accumulation in the oviduct highlights the importance of a species-specific optimum time window for artificial insemination regarding ovulation. Predictions from our extendable in silico experimental system will improve assisted reproduction in humans, endangered species, and livestock.

scholarly journals Neisseria gonorrhoeae Catalase Is Not Required for Experimental Genital Tract Infection despite the Induction of a Localized Neutrophil Response

2007 ◽  
Vol 75 (5) ◽  
pp. 2225-2233 ◽  
Author(s):  
Ángel A. Soler-García ◽  
Ann E. Jerse
Keyword(s):  
Tract Infection ◽  
Neisseria Gonorrhoeae ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Antioxidant Defenses ◽  
Wild Type ◽  
Genital Tract Infection ◽  
Estradiol Treatment ◽  
Significant Difference

ABSTRACT Neisseria gonorrhoeae produces several antioxidant defenses, including high levels of catalase, which may facilitate the persistence during an inflammatory response via neutralization of H2O2 produced by phagocytes. In vivo testing of the role of catalase in gonococcal survival is critical since several physiological factors impact interactions between N. gonorrhoeae and polymorphonuclear leukocytes (PMNs). Here we assessed the importance of gonococcal catalase in a surrogate model of female genital tract infection. Female BALB/c mice were treated with 17-β estradiol to promote susceptibility to N. gonorrhoeae and inoculated intravaginally with wild-type gonococci or a catalase (kat) deletion mutant. A localized PMN influx occurred in an average of 43 and 81% of mice infected with wild-type or kat mutant gonococci, respectively, and PMNs associated with numerous wild-type or catalase-deficient bacteria were observed in vaginal smears. The combined results of six experiments showed a significant difference in the number of days wild-type bacteria were recovered compared to the catalase-deficient gonococci. However, there was much variability between experiments, and we found no correlation between PMN influx, colonization load, and clearance of wild-type or kat mutant bacteria. Estradiol treatment did not impair bacterial uptake, the luminol-dependent chemiluminescence response, or the killing capacity of isolated murine PMNs against N. gonorrhoeae or Staphylococcus aureus. Our data suggest N. gonorrhoeae is not significantly challenged by H2O2 produced by PMNs in the murine lower genital tract; alternatively, redundant defense mechanisms may protect the gonococcus from reactive oxygen species during infection.

Pyometra and estrous cycle modulate the uterine expression of the Kisspeptin system and angiogenic and immune factors in cats

2020 ◽  
Author(s):  
Luciano Cardoso Santos ◽  
Jeane Martinha Anjos Cordeiro ◽  
Larissa Silva Santana ◽  
Larissa Rodrigues Santana ◽  
Bianca Reis Santos ◽  
...  
Keyword(s):  
Estrous Cycle ◽  
Genital Tract ◽  
Functional Relationship ◽  
Female Genital Tract ◽  
Domestic Cat ◽  
Immune Mediators ◽  
Gene And Protein Expression ◽  
Gene Correlation

ABSTRACT Failures in hypothalamic kisspeptin/Kiss1r signaling are associated with infertility, and in vitro studies have shown that kisspeptin can modulate angiogenesis and immune activity. Because there is no in vivo research on the functional relationship between these factors in the reproductive system, especially in domestic cats, we evaluated the expression profile of kisspeptin/Kiss1r and angiogenic and immunological mediators in the genital tract of cyclic cats and of those with pyometra. The uterus of cats in diestrus exhibited greater gene and protein expression of Kiss1, as well as Vegf, Pigf, Mif, and Il6. In contrast, Kiss1r presented greater expression in proestrus/estrus, similarly to that observed for the immunostaining of INFγ, MIF, TNFα, and IL10. These factors were positively correlated with Kiss1 and/or Kiss1r, and a positive correlation between Kiss1 and Kiss1r was also observed in the uterus of cats during the estrous cycle. Cats with pyometra showed greater immunostaining of Kiss1 and Kiss1r on the endometrial surface and reduced immunostaining of Kiss1 in deep glands, whereas there was a significant reduction in Vegf, Pigf, Mif, and Il6 mRNA, and an increase in Tnf mRNA. The findings reveal that there is a gene correlation between kisspeptin/Kiss1r and angiogenic and immune mediators in the uterus of the domestic cat, which are modulated by the estrous cycle, and that pyometra affects the expression of these mediators. This study suggests, for the first time, a functional relationship between the Kiss/Kiss1r system and angiogenic and immune mediators in the female genital tract.

scholarly journals Opacity Proteins Increase Neisseria gonorrhoeae Fitness in the Female Genital Tract Due to a Factor under Ovarian Control

2010 ◽  
Vol 78 (4) ◽  
pp. 1629-1641 ◽  
Author(s):  
Jessica G. Cole ◽  
Nanette B. Fulcher ◽  
Ann E. Jerse
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Reproductive Cycle ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Phase Variable ◽  
Ovariectomized Mice ◽  
Selection Pattern ◽  
Strain Fa1090 ◽  
Female Genital

ABSTRACT The neisserial opacity (Opa) proteins are a family of antigenically distinct outer membrane proteins that undergo phase-variable expression. Opa+ variants of Neisseria gonorrhoeae strain FA1090 are selected in a cyclical pattern from the lower genital tract of estradiol-treated mice. Here we show that cyclical recovery of Opa+ gonococci does not occur in ovariectomized mice; therefore, the reproductive cycle plays a role in the selection kinetics in vivo. As predicted by the selection pattern shown by wild-type gonococci, we demonstrated that a constitutive Opa-expressing strain was more fit than an Opa-deficient mutant in the early and late phases of infection. We found no evidence that Opa-mediated colonization selects for Opa+ variants during murine infection based on adherence assays with cultured murine epithelial cells. We also tested the hypothesis that complement selects for Opa protein expression during infection. Although some Opa+ variants of a serum-sensitive derivative of strain FA1090 were more resistant to the bactericidal activity of normal human serum, selection for Opa expression was not abrogated in C3-depleted mice. Finally, as previously reported, Opa+ gonococci were more sensitive to serine proteases. Thus, proteases or protease inhibitors may contribute to the observed in vivo selection pattern. We concluded that Opa proteins promote persistence of N. gonorrhoeae in the female genital tract and that opa gene phase variation allows gonococci to evade or capitalize upon unidentified host factors of the mammalian reproductive cycle. This work revealed an intimate interaction between pathogen and host and provides evidence that hormonally related factors shape bacterial adaptation.

scholarly journals Sperm migration in the genital tract—In silico experiments identify key factors for reproductive success

2021 ◽  
Vol 17 (7) ◽  
pp. e1009109
Author(s):  
Jorin Diemer ◽  
Jens Hahn ◽  
Björn Goldenbogen ◽  
Karin Müller ◽  
Edda Klipp
Keyword(s):  
Reproductive Success ◽  
In Silico ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Male Gametes ◽  
Sperm Migration ◽  
Sperm Motion ◽  
Female Genital

Sperm migration in the female genital tract controls sperm selection and, therefore, reproductive success as male gametes are conditioned for fertilization while their number is dramatically reduced. Mechanisms underlying sperm migration are mostly unknown, since in vivo investigations are mostly unfeasible for ethical or practical reasons. By presenting a spatio-temporal model of the mammalian female genital tract combined with agent-based description of sperm motion and interaction as well as parameterizing it with bovine data, we offer an alternative possibility for studying sperm migration in silico. The model incorporates genital tract geometry as well as biophysical principles of sperm motion observed in vitro such as positive rheotaxis and thigmotaxis. This model for sperm migration from vagina to oviducts was successfully tested against in vivo data from literature. We found that physical sperm characteristics such as velocity and directional stability as well as sperm-fluid interactions and wall alignment are critical for success, i.e. sperms reaching the oviducts. Therefore, we propose that these identified sperm parameters should be considered in detail for conditioning sperm in artificial selection procedures since the natural processes are normally bypassed in reproductive in vitro technologies. The tremendous impact of mucus flow to support sperm accumulation in the oviduct highlights the importance of a species-specific optimum time window for artificial insemination regarding ovulation. Predictions from our extendable in silico experimental system will improve assisted reproduction in humans, endangered species, and livestock.

scholarly journals Sulfated Polysaccharides and a Synthetic Sulfated Polymer Are Potent Inhibitors of Chlamydia trachomatisInfectivity In Vitro but Lack Protective Efficacy in an In Vivo Murine Model of Chlamydial Genital Tract Infection

1998 ◽  
Vol 66 (3) ◽  
pp. 1258-1260 ◽  
Author(s):  
Hua Su ◽  
Harlan D. Caldwell
Keyword(s):  
Murine Model ◽  
Genital Tract ◽  
Dextran Sulfate ◽  
Protective Efficacy ◽  
Female Genital Tract ◽  
Sulfated Polysaccharides ◽  
Genital Tract Infection ◽  
Female Genital

ABSTRACT Heparin, dextran sulfate, pentosan polysulfate, and a sulfated synthetic copolymer of acrylic acid and vinyl alcohol were shown to be potent inhibitors of Chlamydia trachomatis infectivity for cultured human epithelial cells. Despite their potent antichlamydial activity in vitro, neither heparin nor dextran sulfate was effective in inhibiting the infectivity of C. trachomatis in a murine model of chlamydial infection of the female genital tract.

scholarly journals Role of Heparan Sulfate in Attachment to and Infection of the Murine Female Genital Tract by Human Papillomavirus

2008 ◽  
Vol 83 (5) ◽  
pp. 2067-2074 ◽  
Author(s):  
Katherine M. Johnson ◽  
Rhonda C. Kines ◽  
Jeffrey N. Roberts ◽  
Douglas R. Lowy ◽  
John T. Schiller ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Basement Membrane ◽  
Heparan Sulfate ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Surface Binding ◽  
Primary Attachment ◽  
Female Genital

ABSTRACT The host factors required for in vivo infection have not been investigated for any papillomavirus. Using a recently developed murine cervicovaginal challenge model, we evaluated the importance of heparan sulfate proteoglycans (HSPGs) in human papillomavirus (HPV) infection of the murine female genital tract. We examined HPV type 16 (HPV16) as well as HPV31 and HPV5, for which some evidence suggests that they may differ from HPV16 in their utilization of HSPGs as their primary attachment factor in vitro. Luciferase-expressing pseudovirus of all three types infected the mouse genital tract, although HPV5, which normally infects nongenital epidermis, was less efficient. Heparinase III treatment of the genital tract significantly inhibited infection of all three types by greater than 90% and clearly inhibited virion attachment to the basement membrane and cell surfaces, establishing that HSPGs are the primary attachment factors for these three viruses in vivo. However, the pseudoviruses differed in their responses to treatment with various forms of heparin, a soluble analog of heparan sulfate. HPV16 and HPV31 infections were effectively inhibited by a highly sulfated form of heparin, but HPV5 was not, although it bound the compound. In contrast, a N-desulfated and N-acylated variant preferentially inhibited HPV5. Inhibition of infection paralleled the relative ability of the variants to inhibit basement membrane and cell surface binding. We speculate that cutaneous HPVs, such as HPV5, and genital mucosal HPVs, such as HPV16 and -31, may have evolved to recognize different forms of HSPGs to enable them to preferentially infect keratinocytes at different anatomical sites.

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