Critical role of Th17 responses in a murine model of Neisseria gonorrhoeae genital infection

Feinen, Brandon; Jerse, Ann E.; Gaffen, Sarah L.; Russell, Michael W.

doi:10.1038/mi.2009.139

Cited by 118 publications

(193 citation statements)

References 54 publications

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“…In the current study, we used three independent experimental approaches to show that T cells producing IL-17 and IL-22 are also dramatically reduced in the cervix of HIV + women. The clinical impact of this mucosal depletion is not clear, but because Th17 cells are critical mediators of protection against mucosal fungal and bacterial infection (19,44,45), this suggests that the lack of Th17 and Th22 cells in the cervix may contribute to the increased frequency of candidiasis and other genital tract infections that is seen in HIV + women (46). Although we demonstrated that Th17 and Th22 are preferentially depleted from the female genital tract during HIV infection, because these subsets were defined by the production of IL-17 and IL-22, respectively, the possibility remains that these cells were present in the cervix but functionally impaired.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Human Cervical CD4+ T Cell Subset Coexpressing Multiple Markers of HIV Susceptibility

McKinnon

Nyanga

Chege

et al. 2011

The Journal of Immunology

160

158

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The HIV pandemic disproportionately affects women, with most infections acquired through receptive vaginal sex. Although the target cells by which HIV establishes infection in the female genital tract remain poorly defined, it is known that immune activation results in CD4+ T cells with enhanced susceptibility, as does expression of the mucosal integrin α4β7 and the HIV coreceptor CCR5. Blood and cervical cytobrush specimens were collected from female sex workers (FSWs) in Nairobi, Kenya. Genital infection diagnostics were performed, T cell populations were defined by multiparameter flow cytometry based on their expression of surface receptors relevant to mucosal homing and/or HIV acquisition, and cytokine production was assayed by intracellular cytokine staining. The integrin α4β7 was expressed on 26.0% of cervical CD4+ T cells, and these cells were more likely to express both the HIV coreceptor CCR5 (p < 0.0001) and the early activation marker CD69 (p < 0.0001) but not CXCR4 (p = 0.34). Cervical Th17 frequencies were enhanced compared with blood (7.02 versus 1.24%; p < 0.0001), and cervical IL-17A+ CD4+ T cells preferentially coexpressed α4β7 and CCR5. Expression of IFN-γ and IL-22 was greater in cervical Th17 cells than in blood Th17 cells. In keeping with the hypothesis that these cells are preferential HIV targets, gp120 preferentially bound CCR5+ cervical T cells, and cervical Th17 cells were almost completely depleted in HIV+ FSWs compared with HIV− FSWs. In summary, a subset of Th17 CD4+ T cells in the cervical mucosa coexpresses multiple HIV susceptibility markers; their dramatic depletion after HIV infection suggests that these may serve as key target cells during HIV transmission.

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Section: Discussionmentioning

confidence: 99%

Characterization of a Human Cervical CD4+ T Cell Subset Coexpressing Multiple Markers of HIV Susceptibility

McKinnon

Nyanga

Chege

et al. 2011

The Journal of Immunology

160

158

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“…In addition to subcutaneous injection of estradiol in sesame oil suspension, injection of water-soluble estradiol in PBS and intradermal implantation of a controlled-release estradiol pellet are alternative methods for estrogen administration and have been employed in other mouse models of female genital tract infections 10,35 . Requirement of high estrogen in this model may be explained by two physiological factors.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to C. albicans-induced vaginitis, infections by other pathogens of the female lower genital tract, including Neisseria gonorrhoeae, Trichomonas vaginalis and Herpes simplex virus have been studied using mouse models where the organisms are intravaginally introduced in hormone-treated mice 1,7,10,22,26,35,38 . Therefore, the techniques that are useful for studies involving Candida vaginitis can be applied to and potentially advance methodologies to study pathogenesis and host immune responses for other infectious diseases of the female lower genital tract.…”

Section: Discussionmentioning

confidence: 99%

Protocols for Vaginal Inoculation and Sample Collection in the Experimental Mouse Model of <em>Candida</em> vaginitis

Yano

Fidel

2011

JoVE

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Vulvovaginal candidiasis (VVC), caused by Candida species, is a fungal infection of the lower female genital tract that affects approximately 75% of otherwise healthy women during their reproductive years 18,[32][33][34] . Predisposing factors include antibiotic usage, uncontrolled diabetes and disturbance in reproductive hormone levels due to pregnancy, oral contraceptives or hormone replacement therapies 33,34 . Recurrent VVC (RVVC), defined as three or more episodes per year, affects a separate 5 to 8% of women with no predisposing factors 33 .An experimental mouse model of VVC has been established and used to study the pathogenesis and mucosal host response to Candida 3,4,11,16,17,19,21,25,37 . This model has also been employed to test potential antifungal therapies in vivo 13,24 . The model requires that the animals be maintained in a state of pseudoestrus for optimal Candida colonization/infection 6,14,23 . Under such conditions, inoculated animals will have detectable vaginal fungal burden for weeks to months. Past studies show an extremely high parallel between the animal model and human infection relative to immunological and physiological properties 3,16,21 . Differences, however, include a lack of Candida as normal vaginal flora and a neutral vaginal pH in the mice.Here, we demonstrate a series of key methods in the mouse vaginitis model that include vaginal inoculation, rapid collection of vaginal specimens, assessment of vaginal fungal burden, and tissue preparations for cellular extraction/isolation. This is followed by representative results for constituents of vaginal lavage fluid, fungal burden, and draining lymph node leukocyte yields. With the use of anesthetics, lavage samples can be collected at multiple time points on the same mice for longitudinal evaluation of infection/colonization. Furthermore, this model requires no immunosuppressive agents to initiate infection, allowing immunological studies under defined host conditions. Finally, the model and each technique introduced here could potentially give rise to use of the methodologies to examine other infectious diseases of the lower female genital tract (bacterial, parasitic, viral) and respective local or systemic host defenses. Video LinkThe video component of this article can be found at

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“…Recent studies in the murine model of gonococcal genital tract infection showed that Th17 cells are involved in the immune response to N. gonorrhoeae. This response leads to IL-17 dependent secretion of IL-6, LIX and MIP2 and subsequent recruitment of PMNn, which is delayed in the presence of IL-17A blocking antibodies or deletion of IL-17RA prolonging infection (Feinen et al, 2010).…”

Section: N Gonorrhoeae Mice Infectionmentioning

confidence: 99%

“…Increased of neutrophils and macrophage in site of infection (Song et al, 2008) N. gonorrhoeae mice infection IgG>IgA>IgM in vaginal fluid (Song et al, 2008) Whole-protein extractes of N. gonorrhoeae P9-17 Low titers of IgG in serum (Imarai et al, 2008) N. gonorrhoeae Th17 profile immune response and increased IL-17 (Feinen et al, 2010) IgA1 protease Th1 pro-inflammatory profile with increased IFN and TNF (Tsirpouchtsidis et al, 2002) IgA1 protease IL-1 , IL-6, TNF and IL-8 (Lorenzen et al, 1999) Porin Th2 Similarly, in the murine model of infection, no antibody induced response has been detected. In Balb/c mice, N. gonorrhoeae is able to reach the upper genital organs and to invade uterine tissue, as it occurs in humans (Imarai et al, 2008;Jerse, 1999).…”

Section: N Gonorrhoeae Mice Infectionmentioning

confidence: 99%

Mucosal Immunity and Evasion Strategies of Neisseria gonorrhoeae

Imarai¹,

Acuña²,

Escobar³

et al. 2012

Sexually Transmitted Infections

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Critical role of Th17 responses in a murine model of Neisseria gonorrhoeae genital infection

Cited by 118 publications

References 54 publications

Characterization of a Human Cervical CD4+ T Cell Subset Coexpressing Multiple Markers of HIV Susceptibility

Characterization of a Human Cervical CD4+ T Cell Subset Coexpressing Multiple Markers of HIV Susceptibility

Protocols for Vaginal Inoculation and Sample Collection in the Experimental Mouse Model of <em>Candida</em> vaginitis

Mucosal Immunity and Evasion Strategies of Neisseria gonorrhoeae

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