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

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.

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

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/s1064744995000548 ◽

1995 ◽

Vol 3 (4) ◽

pp. 169-174 ◽

Cited By ~ 12

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.

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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

Infection and Immunity ◽

10.1128/iai.66.3.1258-1260.1998 ◽

1998 ◽

Vol 66 (3) ◽

pp. 1258-1260 ◽

Cited By ~ 14

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.

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

Journal of Virology ◽

10.1128/jvi.02190-08 ◽

2008 ◽

Vol 83 (5) ◽

pp. 2067-2074 ◽

Cited By ~ 145

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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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

Infection and Immunity ◽

10.1128/iai.70.5.2549-2558.2002 ◽

2002 ◽

Vol 70 (5) ◽

pp. 2549-2558 ◽

Cited By ~ 39

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.

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

mBio ◽

10.1128/mbio.00892-13 ◽

2013 ◽

Vol 4 (6) ◽

Cited By ~ 44

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.

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