Susceptibility of Human Female Primary Genital Epithelial Cells to Herpes Simplex Virus, Type-2 and the Effect of TLR3 Ligand and Sex Hormones on Infection1

MacDonald, Erin M; Savoy, Alison; Gillgrass, Amy; Fernandez, Sherie; Śmieja, Marek; Rosenthal, Kenneth L.; Ashkar, Ali A.; Kaushic, Charu

doi:10.1095/biolreprod.107.063933

Cited by 53 publications

(50 citation statements)

References 38 publications

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“…Detailed protocols for isolation and culture of primary GECs have been described previously (21,22). Briefly, endometrial and endocervical tissues were minced into small pieces and digested in an enzyme mixture at 37˚C with shaking.…”

Section: Primary Gec Culturesmentioning

confidence: 99%

HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

Nazli

Kafka

Ferreira

et al. 2013

The Journal of Immunology

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120

118

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Although women constitute half of all HIV-1–infected people worldwide (UNAIDS World AIDS Day Report, 2011), the earliest events in the female reproductive tract (FRT) during heterosexual HIV-1 transmission are poorly understood. Recently, we demonstrated that HIV-1 could directly impair the mucosal epithelial barrier in the FRT. This suggested that the HIV-1 envelope glycoprotein gp120 was being recognized by a membrane receptor on genital epithelial cells, leading to innate immune activation. In this study, we report that pattern-recognition receptors TLR2 and -4 bind to HIV-1 gp120 and trigger proinflammatory cytokine production via activation of NF-κB. The gp120–TLR interaction also required the presence of heparan sulfate (HS). Bead-binding assays showed that gp120 can bind to HS, TLR2, and TLR4, and studies in transfected HEK293 cells demonstrated that HS and TLR2 and -4 were necessary to mediate downstream signaling. Exposure to seminal plasma from HIV-1–infected and uninfected men with gp120 added to it induced a significant proinflammatory cytokine response from genital epithelial cells and disruption of tight junctions, indicating a role for gp120 in mucosal barrier disruption during HIV-1 heterosexual transmission. These studies provide, for the first time to our knowledge, a possible mechanism by which HIV-1 gp120 could directly initiate innate immune activation in the FRT during heterosexual transmission.

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Section: Primary Gec Culturesmentioning

confidence: 99%

HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

Nazli

Kafka

Ferreira

et al. 2013

The Journal of Immunology

Self Cite

120

118

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show abstract

“…Treatment with estradiol increases HSV-2 infection in human endometrial epithelium cells and viral shedding is decreased following treatment with progesterone (MacDonald et al 2007). This suggests that the effects of sex hormones on the immune response to HSV-2 in humans and mice are different, and perhaps opposite, and may explain the prevalence of HSV-2 infection in human females.…”

Section: Viral Infectionsmentioning

confidence: 99%

Gender Specific Differences in the Immune Response to Infection

McClelland

Smith

2011

Arch. Immunol. Ther. Exp.

157

134

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There are many instances where males and females differ in the susceptibility to infections. The reason for these differences in susceptibility is multifactorial. The primary cause is thought to be due to differences induced by sex hormones and their effects on gene expression as well as the immune system, but may also be due to innate physiological differences between males and females. This review summarizes gender specific differences seen in infections caused by bacteria, fungi, parasites and viruses. Ultimately, gender specific differences appear to be dependent on the microbe causing the infection, as not every infection with a specific microbial type results in increased susceptibility of one gender over the other. This suggests that there is an interaction between gender specific immune differences and the specific immune response to individual microbes.

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“…In particular, the simple columnar epithelial cells of the endocervix constitutively express IL-6, IL-8, and RANTES genes [5], with the endocervical cells being more active in cytokine secretion than the ectocervical cells [7], [8]. Pathogens such as herpes simplex virus (HSV), human papillomavirus (HPV), and HIV have been shown to infect epithelial cells of the FRT and the process is affected by treatment with hormones such as progesterone (P4) [9], [10].…”

Section: Introductionmentioning

confidence: 99%

The Injectable-Only Contraceptive Medroxyprogesterone Acetate, Unlike Norethisterone Acetate and Progesterone, Regulates Inflammatory Genes in Endocervical Cells via the Glucocorticoid Receptor

et al. 2014

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Clinical studies suggest that the injectable contraceptive medroxyprogesterone acetate (MPA) increases susceptibility to infections such as HIV-1, unlike the injectable contraceptive norethisterone enanthate (NET-EN). We investigated the differential effects, molecular mechanism of action and steroid receptor involvement in gene expression by MPA as compared to NET and progesterone (P4) in the End1/E6E7 cell line model for the endocervical epithelium, a key point of entry for pathogens in the female genital mucosa. MPA, unlike NET-acetate (NET-A) and P4, increases mRNA expression of the anti-inflammatory GILZ and IκBα genes. Similarly, MPA unlike NET-A, decreases mRNA expression of the pro-inflammatory IL-6, IL-8 and RANTES genes, and IL-6 and IL-8 protein levels. The predominant steroid receptor expressed in the End1/E6E7 and primary endocervical epithelial cells is the glucocorticoid receptor (GR), and GR knockdown experiments show that the anti-inflammatory effects of MPA are mediated by the GR. Chromatin-immunoprecipitation results suggest that MPA, unlike NET-A and P4, represses pro-inflammatory cytokine gene expression in cervical epithelial cells via a mechanism involving recruitment of the GR to cytokine gene promoters, like the GR agonist dexamethasone. This is at least in part consistent with direct effects on transcription, without a requirement for new protein synthesis. Dose response analysis shows that MPA has a potency of ∼24 nM for transactivation of the anti-inflammatory GILZ gene and ∼4–20 nM for repression of the pro-inflammatory genes, suggesting that these effects are likely to be relevant at injectable contraceptive doses of MPA. These findings suggest that in the context of the genital mucosa, these GR-mediated glucocorticoid-like effects of MPA in cervical epithelial cells are likely to play a critical role in discriminating between the effects on inflammation caused by different progestins and P4 and hence susceptibility to genital infections, given the predominant expression of the GR in primary endocervical epithelial cells.

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Susceptibility of Human Female Primary Genital Epithelial Cells to Herpes Simplex Virus, Type-2 and the Effect of TLR3 Ligand and Sex Hormones on Infection1

Cited by 53 publications

References 38 publications

HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

Gender Specific Differences in the Immune Response to Infection

The Injectable-Only Contraceptive Medroxyprogesterone Acetate, Unlike Norethisterone Acetate and Progesterone, Regulates Inflammatory Genes in Endocervical Cells via the Glucocorticoid Receptor

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