Interferon-β induced in female genital epithelium by HIV-1 glycoprotein 120 via Toll-like-receptor 2 pathway acts to protect the mucosal barrier

Nazli, Aisha; Dizzell, Sara; Zahoor, Muhammad Atif; Ferreira, Victor H; Kafka, Jessica K.; Woods, Matthew; Ouellet, Michel; Ashkar, Ali A.; Tremblay, Michel J.; Bowdish, Dawn M. E.; Kaushic, Charu

doi:10.1038/cmi.2017.168

Cited by 15 publications

(13 citation statements)

References 55 publications

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“…The finding that acute HIV‐1 exposure upregulates GPB5 transcripts in primary endometrial GECs may indicate that GPB5 may also have a similar role in inhibiting HIV‐1 in the FGT. The upregulation of HIV‐1 restriction factors may be mediated by activation of TLR‐2 on endometrial GECs, that induce biologically active IFN‐β and ISGs with anti‐viral and mucosal barrier protective effects, as shown in our recent study . Thus, the outcome of HIV‐1 exposure in the FGT could be determined by the net effect of inflammatory and anti‐viral pathways.…”

Section: Hiv‐1 and Epithelial Barriersupporting

confidence: 51%

Hormonal influence on HIV‐1 transmission in the female genital tract: New insights from systems biology

Dupont

Lam

Woods

et al. 2018

American J Rep Immunol

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Although anti-retroviral treatments have significantly slowed down the spread of the HIV-1 pandemic, approximately 2 million new infections occur every year. The majority of new infections are in sub-Saharan Africa where rates of infection are much higher in women than men. Young women are disproportionately affected and have higher susceptibility to HIV-1. The complex interactions between HIV-1 and the female genital tract (FGT) and the mechanisms regulating susceptibility in women remain incompletely understood. In this review, we focus on the current understanding of the acute events that occur in the FGT following HIV-1 exposure with a particular focus on the effect of endogenous and exogenous sex hormones on HIV-1 susceptibility. We highlight the contribution of the recent transcriptomic and proteomic studies in providing new insights.

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Section: Hiv‐1 and Epithelial Barriersupporting

confidence: 51%

Hormonal influence on HIV‐1 transmission in the female genital tract: New insights from systems biology

Dupont

Lam

Woods

et al. 2018

American J Rep Immunol

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“…Indeed, epithelial cells from both the upper and lower FGT have been reported to activate signaling pathways following pathogen exposure ( Ferreira et al, 2013 ; Nazli et al, 2010 , 2009 ). Furthermore, our group recently demonstrated that HIV-1 gp120 ( Box 1 ) signaling through TLR2 induced interferon β (IFN-β) production in genital epithelial cells, which had an anti-inflammatory activity and protected the function of the epithelial barrier ( Nazli et al, 2018 ). In addition to inflammatory cytokines, cervicovaginal epithelial cells are known to produce AMPs, including defensins ( Box 1 ), secretory leukocyte protease inhibitor (SLPI), lysozyme, lactoferrin and elafin ( Box 1 ) ( Nguyen et al, 2014 ; Wira et al, 2005 ).…”

Section: Immunity In the Lower Female Genital Tractmentioning

confidence: 99%

The relationship between sex hormones, the vaginal microbiome and immunity in HIV-1 susceptibility in women

Wessels

Felker

Dupont

et al. 2018

Disease Models &Amp; Mechanisms

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The role of sex hormones in regulating immune responses in the female genital tract has been recognized for decades. More recently, it has become increasingly clear that sex hormones regulate susceptibility to sexually transmitted infections through direct and indirect mechanisms involving inflammation and immune responses. The reproductive cycle can influence simian/human immunodeficiency virus (SHIV) infections in primates and HIV-1 infection in ex vivo cervical tissues from women. Exogenous hormones, such as those found in hormonal contraceptives, have come under intense scrutiny because of the increased susceptibility to sexually transmitted infections seen in women using medroxyprogesterone acetate, a synthetic progestin-based contraceptive. Recent meta-analyses concluded that medroxyprogesterone acetate enhanced HIV-1 susceptibility in women by 40%. In contrast, estradiol-containing hormonal contraceptives were not associated with increased susceptibility and some studies reported a protective effect of estrogen on HIV/SIV infection, although the underlying mechanisms remain incompletely understood. Recent studies describe a key role for the vaginal microbiota in determining susceptibility to sexually transmitted infections, including HIV-1. While Lactobacillus spp.-dominated vaginal microbiota is associated with decreased susceptibility, complex microbiota, such as those seen in bacterial vaginosis, correlates with increased susceptibility to HIV-1. Interestingly, sex hormones are inherently linked to microbiota regulation in the vaginal tract. Estrogen has been postulated to play a key role in establishing a Lactobacillus-dominated microenvironment, whereas medroxyprogesterone acetate is linked to hypo-estrogenic effects. The aim of this Review is to contribute to a better understanding of the sex-hormone–microbiome–immunity axis, which can provide key information on the determinants of HIV-1 susceptibility in the female genital tract and, consequently, inform HIV-1 prevention strategies.

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“…However, cervical epithelial cells can detect and react to the virus with recent work detecting IFN being produced mainly on the basal interface of the epithelium in response to HIV exposure. 49 IFN , in this context, protects the epithelial barrier against HIV-mediated damage, which could prevent the HIV from reaching its target cells and thus preventing infection. Once the epithelial barrier is crossed, HIV-1 infects its preferred host cells, CD4+ T cells, dendritic cells and macrophages, where a considerable innate immune response is observed.…”

Section: Hivmentioning

confidence: 99%

“…HIV induces IFN in uterine epithelial cells to protect tight junctions. 49 IFN IFN prevents HIV infection in epithelial, T-cells, and macrophages. 59,60 Rhesus macaques IFN /IFN Simian-HIV induces a primary response includes proinflammatory cytokines, whereas IFN /IFN were induced in a secondary response.…”

Section: Ifnmentioning

confidence: 99%

Type I IFNs in the female reproductive tract: The first line of defense in an ever-changing battleground

Cumming

Bourke

2018

Journal of Leukocyte Biology

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The primary function of the female reproductive tract (FRT) is to enable successful reproduction, yet the biologic mechanisms required to accomplish this, which include fluctuating sex hormones and tolerance of semen and a semi-allogeneic fetus, can leave this unique mucosal environment susceptible to pathogenic challenge. Consequently, the FRT has evolved specialized innate and adaptive immune responses tailored to protecting itself from infection without compromising reproductive success. A family of innate immune cytokines that has emerged as important regulators of these immune responses is the type I IFNs. Type I IFNs are typically rapidly produced in response to pathogenic stimulation and are capable of sculpting pleotropic biologic effects, including immunomodulation, antiproliferative effects, and inducing antiviral and bactericidal molecules. Here, we review what is currently known about type I IFN-mediated immunity in the FRT in human, primate, and murine models and explore their importance with respect to three highly relevant FRT infections: HIV, Zika, and Chlamydia. K E Y W O R D SChlamydia, female reproductive tract, HIV, hormonal regulation, mucosal immunity, Type I IFNs, Zika THE FRT: A DYNAMIC IMMUNE ENVIRONMENTThe female reproductive tract (FRT) is a site of unique mucosal immune regulation; it must be capable of detecting and inducing immune responses against pathogenic infections yet maintain tolerance to commensal bacteria, semen, and the semi-allogeneic fetus. The FRT can be broadly divided into two main anatomic sites: the lower reproductive tract, which includes the vagina and ectocervix, and the upper reproductive tract, which includes the uterus, fallopian tubes, and ovaries. The structure of the lining of the FRT varies considerably between these sites and reflects their respective functional characteristics. The lining of the lower FRT comprises multilayered squamous epithelium, which represents a large barrier defense and supports high levels of commensal microbes. In contrast, the upper FRT comprises a single layer of columnar epithelium, which is remodeled in response to sex hormones to enable support of successful implantation and pregnancy. 1 Between these two sites of the FRT is the transformation zone, where the squamous epithelium of the ectocervix meets the columnar epithelium of the endocervix. FRT immunity is predominately mediated by both epithelial cells and the immune cells that underlie the epithelium in both the upper and lower reproductive tract. REGULATION OF FRT IMMUNITY: SEX HORMONESAn important aspect of immunoregulation within the FRT is that the FRT immune cells are continuously modulated in response to fluctuating levels of the sex hormones estrogen (E2) and progesterone (P4) during the menstrual cycle. The first line of defense against pathogen infection is usually the epithelial cells that line the upper and lower FRT. Epithelial cells that line the vagina and uterus are important regulators of immunity in the mucosa, acting through specialized antigen present...

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Interferon-β induced in female genital epithelium by HIV-1 glycoprotein 120 via Toll-like-receptor 2 pathway acts to protect the mucosal barrier

Cited by 15 publications

References 55 publications

Hormonal influence on HIV‐1 transmission in the female genital tract: New insights from systems biology

Hormonal influence on HIV‐1 transmission in the female genital tract: New insights from systems biology

The relationship between sex hormones, the vaginal microbiome and immunity in HIV-1 susceptibility in women

Type I IFNs in the female reproductive tract: The first line of defense in an ever-changing battleground

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