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The progestin-based hormonal contraceptive Depot Medroxyprogesterone Acetate (DMPA) is widely used in sub-Saharan Africa, where HIV-1 is endemic. Meta-analyses have shown that women using DMPA are 40% more likely than women not using hormonal contraceptives to acquire Human Immunodeficiency Virus (HIV-1). Therefore understanding how DMPA increases susceptibility to HIV-1 is an important public health issue. Using C57BL/6 mice and our previously optimized humanized mouse model (NOD-Rag1 tm1Mom Il2rg tm1Wjl transplanted with hCD34-enriched hematopoietic stem cells; Hu-mice) where peripheral blood and tissues are reconstituted by human immune cells, we assessed how DMPA affected mucosal barrier function, HIV-1 susceptibility, viral titres, and target cells compared to mice in the diestrus phase of the estrous cycle, when endogenous progesterone is highest. We found that DMPA enhanced FITC-dextran dye leakage from the vaginal tract into the systemic circulation, enhanced target cells (hCD68+ macrophages, hCD4+ T cells) in the vaginal tract and peripheral blood (hCD45+hCD3+hCD4+hCCR5+ T cells), increased the rate of intravaginal HIV-1 infection, extended the window of vulnerability, and lowered vaginal viral titres following infection. These findings suggest DMPA may enhance susceptibility to HIV-1 in Hu-mice by impairing the vaginal epithelial barrier, increasing vaginal target cells (including macrophages), and extending the period of time during which Hu-mice are susceptible to infection; mechanisms that might also affect HIV-1 susceptibility in women.
Jocelyn M. Wessels; Philip V. Nguyen; Danielle Vitali; Kristen Mueller; Fatemeh Vahedi; Allison M. Felker; Haley A. Dupont; Puja Bagri; Chris P. Verschoor; Alexandre Deshiere; Tony Mazzulli; Michel J. Tremblay; Ali A. Ashkar; Charu Kaushic. Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice. Scientific Reports 2021, 11, 1 -16.
AMA StyleJocelyn M. Wessels, Philip V. Nguyen, Danielle Vitali, Kristen Mueller, Fatemeh Vahedi, Allison M. Felker, Haley A. Dupont, Puja Bagri, Chris P. Verschoor, Alexandre Deshiere, Tony Mazzulli, Michel J. Tremblay, Ali A. Ashkar, Charu Kaushic. Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice. Scientific Reports. 2021; 11 (1):1-16.
Chicago/Turabian StyleJocelyn M. Wessels; Philip V. Nguyen; Danielle Vitali; Kristen Mueller; Fatemeh Vahedi; Allison M. Felker; Haley A. Dupont; Puja Bagri; Chris P. Verschoor; Alexandre Deshiere; Tony Mazzulli; Michel J. Tremblay; Ali A. Ashkar; Charu Kaushic. 2021. "Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice." Scientific Reports 11, no. 1: 1-16.
Herpes simplex virus type 2 (HSV-2) is the primary cause of genital herpes which results in significant morbidity and mortality, especially in women, worldwide. HSV-2 is transmitted primarily through infection of epithelial cells at skin and mucosal surfaces. Our earlier work to examine interactions between HSV-2 and vaginal epithelial cells demonstrated that infection of the human vaginal epithelial cell line (VK2) with HSV-2 resulted in increased expression of TRIM26, a negative regulator of the Type I interferon pathway. Given that upregulation of TRIM26 could negatively affect anti-viral pathways, we decided to further study the role of TRIM26 in HSV-2 infection and replication. To do this, we designed and generated two cell lines derived from VK2s with TRIM26 overexpressed (OE) and knocked out (KO). Both, along with wildtype (WT) VK2, were infected with HSV-2 and viral titres were measured in supernatants 24 h later. Our results showed significantly enhanced virus production by TRIM26 OE cells, but very little replication in TRIM26 KO cells. We next examined interferon-β production and expression of two distinct interferon stimulated genes (ISGs), MX1 and ISG15, in all three cell lines, prior to and following HSV-2 infection. The absence of TRIM26 (KO) significantly upregulated interferon-β production at baseline and even further after HSV-2 infection. TRIM26 KO cells also showed significant increase in the expression of MX1 and ISG15 before and after HSV-2 infection. Immunofluorescent staining indicated that overexpression of TRIM26 substantially decreased the nuclear localization of IRF3, the primary mediator of ISG activation, before and after HSV-2 infection. Taken together, our data indicate that HSV-2 utilizes host factor TRIM26 to evade anti-viral response and thereby increase its replication in vaginal epithelial cells.
Tushar Dhawan; Muhammad Atif Zahoor; Nishant Heryani; Samuel Tekeste Workenhe; Aisha Nazli; Charu Kaushic. TRIM26 Facilitates HSV-2 Infection by Downregulating Antiviral Responses through the IRF3 Pathway. Viruses 2021, 13, 70 .
AMA StyleTushar Dhawan, Muhammad Atif Zahoor, Nishant Heryani, Samuel Tekeste Workenhe, Aisha Nazli, Charu Kaushic. TRIM26 Facilitates HSV-2 Infection by Downregulating Antiviral Responses through the IRF3 Pathway. Viruses. 2021; 13 (1):70.
Chicago/Turabian StyleTushar Dhawan; Muhammad Atif Zahoor; Nishant Heryani; Samuel Tekeste Workenhe; Aisha Nazli; Charu Kaushic. 2021. "TRIM26 Facilitates HSV-2 Infection by Downregulating Antiviral Responses through the IRF3 Pathway." Viruses 13, no. 1: 70.
Herpes simplex virus 2 (HSV-2) is a highly prevalent sexually transmitted infection for which there is currently no vaccine available. Interestingly, the female sex hormone estradiol has been shown to be protective against HSV-2. However, the underlying mechanisms by which this occurs remains relatively unknown. Our study demonstrates that under the influence of estradiol treatment, intranasal immunization with an attenuated strain of HSV-2 leads to enhanced establishment of antiviral memory T cell responses in the upper respiratory tract and female reproductive tract. In these sites, estradiol treatment leads to greater T h 17 memory cells, which precede enhanced T h 1 memory responses. Consequently, the T cell responses mounted by tissue-resident memory cells in the female reproductive tract of estradiol-treated mice are sufficient to protect mice against vaginal HSV-2 challenge. This study offers important insights regarding the regulation of mucosal immunity by hormones and on potential strategies for generating optimal immunity during vaccination.
Puja Bagri; Ramtin Ghasemi; Joshua J. C. McGrath; Danya Thayaparan; Emma Yu; Andrew G. Brooks; Martin R. Stämpfli; Charu Kaushic. Estradiol Enhances Antiviral CD4 + Tissue-Resident Memory T Cell Responses following Mucosal Herpes Simplex Virus 2 Vaccination through an IL-17-Mediated Pathway. Journal of Virology 2020, 95, 1 .
AMA StylePuja Bagri, Ramtin Ghasemi, Joshua J. C. McGrath, Danya Thayaparan, Emma Yu, Andrew G. Brooks, Martin R. Stämpfli, Charu Kaushic. Estradiol Enhances Antiviral CD4 + Tissue-Resident Memory T Cell Responses following Mucosal Herpes Simplex Virus 2 Vaccination through an IL-17-Mediated Pathway. Journal of Virology. 2020; 95 (1):1.
Chicago/Turabian StylePuja Bagri; Ramtin Ghasemi; Joshua J. C. McGrath; Danya Thayaparan; Emma Yu; Andrew G. Brooks; Martin R. Stämpfli; Charu Kaushic. 2020. "Estradiol Enhances Antiviral CD4 + Tissue-Resident Memory T Cell Responses following Mucosal Herpes Simplex Virus 2 Vaccination through an IL-17-Mediated Pathway." Journal of Virology 95, no. 1: 1.
Medroxyprogesterone acetate (MPA) is a frequently used hormonal contraceptive that has been shown to significantly increase HIV-1 susceptibility by approximately 40 %. However, the underlying mechanism by which this occurs remains unknown. Here, we examined the biological response to MPA by vaginal epithelial cells, the first cells to encounter HIV-1 during sexual transmission, in order to understand the potential mechanism(s) of MPA-mediated increase of HIV-1 infection. Using microarray analysis and in vitro assays, we characterized the response of vaginal epithelial cells, grown in biologically relevant air-liquid interface (ALI) cultures, to physiological levels of female sex hormones, estradiol (E2), progesterone (P4), or MPA. Transcriptional profiling of E2, P4 or MPA-treated vaginal epithelial cells indicated unique transcriptional profiles associated with each hormone. MPA treatment increased transcripts of genes related to cholesterol/sterol synthesis and decreased transcripts related to cell division and cell-cell adhesion, results not seen with E2 or P4 treatments. MPA treatment also resulted in unique gene expression indicative of decreased barrier integrity. Functional assays confirmed that MPA, but not E2 or P4 treatments, resulted in increased epithelial barrier permeability and inhibited cell cycle progression. The effects of MPA on vaginal epithelial cells seen in this study may help explain the increase of HIV-1 infection in women who use MPA as a hormonal contraceptive.
Matthew William Woods; Muhammad Atif Zahoor; Jeffrey Lam; Puja Bagri; Haley Dupont; Chris P. Verschoor; Aisha Nazli; Charu Kaushic. Transcriptional response of vaginal epithelial cells to medroxyprogesterone acetate treatment results in decreased barrier integrity. Journal of Reproductive Immunology 2020, 143, 103253 .
AMA StyleMatthew William Woods, Muhammad Atif Zahoor, Jeffrey Lam, Puja Bagri, Haley Dupont, Chris P. Verschoor, Aisha Nazli, Charu Kaushic. Transcriptional response of vaginal epithelial cells to medroxyprogesterone acetate treatment results in decreased barrier integrity. Journal of Reproductive Immunology. 2020; 143 ():103253.
Chicago/Turabian StyleMatthew William Woods; Muhammad Atif Zahoor; Jeffrey Lam; Puja Bagri; Haley Dupont; Chris P. Verschoor; Aisha Nazli; Charu Kaushic. 2020. "Transcriptional response of vaginal epithelial cells to medroxyprogesterone acetate treatment results in decreased barrier integrity." Journal of Reproductive Immunology 143, no. : 103253.
Herpes Simplex Virus Type 2 (HSV-2) is one of the most prevalent sexually transmitted viruses and is a known risk factor for HIV acquisition in the Female Genital Tract (FGT). Previously, we found that curcumin can block HSV-2 infection and abrogate the production of inflammatory cytokines and chemokines by genital epithelial cells in vitro. In this study, we investigated whether curcumin, encapsulated in nanoparticles and delivered by various in vivo routes, could minimize inflammation and prevent or reduce HSV-2 infection in the FGT. Female mice were pre-treated with curcumin nanoparticles through oral, intraperitoneal and intravaginal routes, and then exposed intravaginally to the tissue inflammation stimulant CpG-oligodeoxynucleotide (ODN). Local intravaginal delivery of curcumin nanoparticles, but not intraperitoneal or oral delivery, reduced CpG-mediated inflammatory histopathology and decreased production of pro-inflammatory cytokines Interleukin (IL)-6, Tumor Necrosis Factor Alpha (TNF-α) and Monocyte Chemoattractant Protein-1 (MCP-1) in the FGT. However, curcumin nanoparticles did not demonstrate anti-viral activity nor reduce tissue pathology when administered prior to intravaginal HSV-2 infection. In an alternative approach, intravaginal pre-treatment with crude curcumin or solid dispersion formulations of curcumin demonstrated increased survival and delayed pathology following HSV-2 infection. Our results suggest that curcumin nanoparticle delivery in the vaginal tract could reduce local tissue inflammation. The anti-inflammatory properties of curcumin delivered to the vaginal tract could potentially reduce the severity of HSV-2 infection and decrease the risk of HIV acquisition in the FGT of women.
Danielle Vitali; Puja Bagri; Jocelyn M. Wessels; Meenakshi Arora; Raghu Ganugula; Ankit Parikh; Talveer Mandur; Allison Felker; Sanjay Garg; M.N.V. Ravi Kumar; Charu Kaushic. Curcumin Can Decrease Tissue Inflammation and the Severity of HSV-2 Infection in the Female Reproductive Mucosa. International Journal of Molecular Sciences 2020, 21, 337 .
AMA StyleDanielle Vitali, Puja Bagri, Jocelyn M. Wessels, Meenakshi Arora, Raghu Ganugula, Ankit Parikh, Talveer Mandur, Allison Felker, Sanjay Garg, M.N.V. Ravi Kumar, Charu Kaushic. Curcumin Can Decrease Tissue Inflammation and the Severity of HSV-2 Infection in the Female Reproductive Mucosa. International Journal of Molecular Sciences. 2020; 21 (1):337.
Chicago/Turabian StyleDanielle Vitali; Puja Bagri; Jocelyn M. Wessels; Meenakshi Arora; Raghu Ganugula; Ankit Parikh; Talveer Mandur; Allison Felker; Sanjay Garg; M.N.V. Ravi Kumar; Charu Kaushic. 2020. "Curcumin Can Decrease Tissue Inflammation and the Severity of HSV-2 Infection in the Female Reproductive Mucosa." International Journal of Molecular Sciences 21, no. 1: 337.
Background & Aims T-regulatory (Treg) cells suppress the immune response to maintain homeostasis. There are 2 main subsets of Treg cells: FOXP3 (forkhead box protein 3)-positive Treg cells, which do not produce high levels of effector cytokines, and type 1 Treg (Tr1) cells, which are FOXP3-negative and secrete interleukin (IL) 10. IL10 is an anti-inflammatory cytokine, so Tr1 cells might be used in the treatment of inflammatory bowel diseases. We aimed to develop methods to isolate and expand human Tr1 cells and define their functions. Methods We obtained blood and colon biopsy samples from patients with Crohn's disease or ulcerative colitis or healthy individuals (controls). CD4+ T cells were isolated from blood samples and stimulated with anti-CD3 and anti-CD28 beads, and Tr1 cells were purified by using an IL10 cytokine-capture assay and cell sorting. FOXP3-positive Treg cells were sorted as CD4+CD25highCD127low cells from unstimulated cells. Tr1 and FOXP3-positive Treg cells were expanded, and phenotypes and gene expression profiles were compared. T cells in peripheral blood mononuclear cells from healthy donors were stimulated with anti-CD3 and anti-CD28 beads, and the suppressive abilities of Tr1 and FOXP3-positive Treg cells were measured. Human colon organoid cultures were established, cultured with supernatants from Tr1 or FOXP3-positive cells, and analyzed by immunofluorescence and flow cytometry. T84 cells (human colon adenocarcinoma epithelial cells) were incubated with supernatants from Tr1 or FOXP3-positive cells, and transepithelial electrical resistance was measured to determine epithelial cell barrier function. Results Phenotypes of Tr1 cells isolated from control individuals vs patients with Crohn's disease or ulcerative colitis did not differ significantly after expansion. Tr1 cells and FOXP3-positive Treg cells suppressed proliferation of effector T cells, but only Tr1 cells suppressed secretion of IL1B and tumor necrosis factor from myeloid cells. Tr1 cells, but not FOXP3-positive Treg cells, isolated from healthy individuals and patients with Crohn's disease or ulcerative colitis secreted IL22, which promoted barrier function of human intestinal epithelial cells. Tr1 cell culture supernatants promoted differentiation of mucin-producing goblet cells in intestinal organoid cultures. Conclusions Human Tr1 cells suppress proliferation of effector T cells (adaptive immune response) and production of IL1B and TNF by myeloid cells (inmate immune response). They also secrete IL22 to promote barrier function. They might be developed as a cell-based therapy for intestinal inflammatory disorders.
Laura Cook; Martin Stahl; Xiao Han; Aisha Nazli; Katherine N. MacDonald; May Q. Wong; Kevin Tsai; Sara Dizzell; Kevan Jacobson; Brian Bressler; Charu Kaushic; Bruce Vallance; Ted Steiner; Megan K. Levings. Suppressive and Gut-Reparative Functions of Human Type 1 T Regulatory Cells. Gastroenterology 2019, 157, 1584 -1598.
AMA StyleLaura Cook, Martin Stahl, Xiao Han, Aisha Nazli, Katherine N. MacDonald, May Q. Wong, Kevin Tsai, Sara Dizzell, Kevan Jacobson, Brian Bressler, Charu Kaushic, Bruce Vallance, Ted Steiner, Megan K. Levings. Suppressive and Gut-Reparative Functions of Human Type 1 T Regulatory Cells. Gastroenterology. 2019; 157 (6):1584-1598.
Chicago/Turabian StyleLaura Cook; Martin Stahl; Xiao Han; Aisha Nazli; Katherine N. MacDonald; May Q. Wong; Kevin Tsai; Sara Dizzell; Kevan Jacobson; Brian Bressler; Charu Kaushic; Bruce Vallance; Ted Steiner; Megan K. Levings. 2019. "Suppressive and Gut-Reparative Functions of Human Type 1 T Regulatory Cells." Gastroenterology 157, no. 6: 1584-1598.
Approximately 40% of global HIV-1 transmission occurs in the female genital tract (FGT) through heterosexual transmission. Epithelial cells lining the FGT provide the first barrier to HIV-1 entry. Previous studies have suggested that certain hormonal contraceptives or a dysbiosis of the vaginal microbiota can enhance HIV-1 acquisition in the FGT. We examined the effects of lactobacilli and female sex hormones on the barrier functions and innate immune responses of primary endometrial genital epithelial cells (GECs). Two probiotic strains, Lactobacillus reuteri RC-14 and L. rhamnosus GR-1, were tested, as were sex hormones estrogen (E2), progesterone (P4), and the hormonal contraceptive medroxyprogesterone acetate (MPA). Our results demonstrate that probiotic lactobacilli enhance barrier function without affecting cytokines. Treatment of GECs with MPA resulted in reduced barrier function. In contrast, E2 treatment enhanced barrier function and reduced production of proinflammatory cytokines. Comparison of hormones plus lactobacilli as a pre-treatment prior to HIV exposure revealed a dominant effect of lactobacilli in preventing loss of barrier function by GECs. In summary, the combination of E2 and lactobacilli had the best protective effect against HIV-1 seen by enhancement of barrier function and reduction in proinflammatory cytokines. These studies provide insights into how probiotic lactobacilli in the female genital microenvironment can alter HIV-1-mediated barrier disruption and how the combination of E2 and lactobacilli may decrease susceptibility to primary HIV infection.
Sara Dizzell; Aisha Nazli; Gregor Reid; Charu Kaushic. Protective Effect of Probiotic Bacteria and Estrogen in Preventing HIV-1-Mediated Impairment of Epithelial Barrier Integrity in Female Genital Tract. Cells 2019, 8, 1120 .
AMA StyleSara Dizzell, Aisha Nazli, Gregor Reid, Charu Kaushic. Protective Effect of Probiotic Bacteria and Estrogen in Preventing HIV-1-Mediated Impairment of Epithelial Barrier Integrity in Female Genital Tract. Cells. 2019; 8 (10):1120.
Chicago/Turabian StyleSara Dizzell; Aisha Nazli; Gregor Reid; Charu Kaushic. 2019. "Protective Effect of Probiotic Bacteria and Estrogen in Preventing HIV-1-Mediated Impairment of Epithelial Barrier Integrity in Female Genital Tract." Cells 8, no. 10: 1120.
IL-17 can be produced by adaptive immune cells such as Th17 cells and by immune cells that produce IL-17 without prior priming. This latter category, which we will refer to as "innate," includes innate cells such as NK cells and innate lymphoid cells and innate-like T cell populations such as NKT cells and γδ+ T cells. Studies in mucosal tissues have shown that the induction of Th17 immunity is amplified by innate IL-17 produced within those tissues. However, the role of innate IL-17 and its effect on Th17 induction in the female genital tract (FGT) is largely unknown. In this study, we characterize the primary source of IL-17-secreting vaginal cells and show that innate IL-17 plays a critical role in priming adaptive Th17 responses in the FGT. Under homeostatic conditions, γδ+ T cells were the predominant source of innate IL-17 in the murine FGT, and this population was modulated by both the sex hormone estradiol and the presence of commensal microbiota. Compared with wild-type C57BL/6 mice, vaginal APCs isolated from IL-17A-deficient (IL-17A-/- ) mice were severely impaired at priming Th17 responses in APC-T cell cocultures. Furthermore, the defect in Th17 induction in the absence of innate IL-17 was associated with impairment of IL-1β production by vaginal CD11c+ dendritic cells. Overall, our study describes a novel role for IL-17 in the FGT and further demonstrates the importance of factors in the vaginal microenvironment that can influence adaptive immune responses.
Varun C. Anipindi; Puja Bagri; Sara E. Dizzell; Rodrigo Jiménez-Saiz; Manel Jordana; Denis P. Snider; Martin R. Stämpfli; Charu Kaushic. IL-17 Production by γδ+ T Cells Is Critical for Inducing Th17 Responses in the Female Genital Tract and Regulated by Estradiol and Microbiota. ImmunoHorizons 2019, 3, 317 -330.
AMA StyleVarun C. Anipindi, Puja Bagri, Sara E. Dizzell, Rodrigo Jiménez-Saiz, Manel Jordana, Denis P. Snider, Martin R. Stämpfli, Charu Kaushic. IL-17 Production by γδ+ T Cells Is Critical for Inducing Th17 Responses in the Female Genital Tract and Regulated by Estradiol and Microbiota. ImmunoHorizons. 2019; 3 (7):317-330.
Chicago/Turabian StyleVarun C. Anipindi; Puja Bagri; Sara E. Dizzell; Rodrigo Jiménez-Saiz; Manel Jordana; Denis P. Snider; Martin R. Stämpfli; Charu Kaushic. 2019. "IL-17 Production by γδ+ T Cells Is Critical for Inducing Th17 Responses in the Female Genital Tract and Regulated by Estradiol and Microbiota." ImmunoHorizons 3, no. 7: 317-330.
The hormonal contraceptive Medroxyprogesterone Acetate (MPA) is associated with increased risk of Human Immunodeficiency Virus (HIV), via incompletely understood mechanisms. Increased diversity in the vaginal microbiota modulates genital inflammation and is associated with increased HIV-1 acquisition. However, the effect of MPA on diversity of the vaginal microbiota is relatively unknown. In a cohort of female Kenyan sex workers, negative for sexually transmitted infections (STIs), with Nugent Scores <7 (N=58 of 370 screened), MPA correlated with significantly increased diversity of the vaginal microbiota as assessed by 16S rRNA gene sequencing. MPA was also significantly associated with decreased levels of estrogen in the plasma, and low vaginal glycogen and α-amylase, factors implicated in vaginal colonization by lactobacilli, bacteria believed to protect against STIs. In a humanized mouse model, MPA treatment was associated with low serum estrogen, low glycogen, and enhanced HIV-1 susceptibility. The mechanism by which the MPA mediated changes in the vaginal microbiota may contribute to HIV-1 susceptibility in this cohort of Kenyan sex workers with Nugent Scores <7 appears to be independent of inflammatory cytokines and/or activated T cells. Altogether these results suggest MPA-induced hypo-estrogenism may alter key metabolic components necessary for vaginal colonization by certain bacterial species including lactobacilli, and allow for greater bacterial diversity in the vaginal microbiota.
Jocelyn M. Wessels; Julie Lajoie; Maeve I. J. Hay Cooper; Kenneth Omollo; Allison M. Felker; Danielle Vitali; Haley A. Dupont; Philip V. Nguyen; Kristen Mueller; Fatemeh Vahedi; Joshua Kimani; Julius Oyugi; Juliana Cheruiyot; John N. Mungai; Alexandre Deshiere; Michel J. Tremblay; Tony Mazzulli; Jennifer C. Stearns; Ali A. Ashkar; Keith R. Fowke; Michael G. Surette; Charu Kaushic. Medroxyprogesterone acetate alters the vaginal microbiota and microenvironment in a Kenyan sex worker cohort and is also associated with increased susceptibility to HIV-1 in humanized mice. Disease Models & Mechanisms 2019, 12, dmm.039669 .
AMA StyleJocelyn M. Wessels, Julie Lajoie, Maeve I. J. Hay Cooper, Kenneth Omollo, Allison M. Felker, Danielle Vitali, Haley A. Dupont, Philip V. Nguyen, Kristen Mueller, Fatemeh Vahedi, Joshua Kimani, Julius Oyugi, Juliana Cheruiyot, John N. Mungai, Alexandre Deshiere, Michel J. Tremblay, Tony Mazzulli, Jennifer C. Stearns, Ali A. Ashkar, Keith R. Fowke, Michael G. Surette, Charu Kaushic. Medroxyprogesterone acetate alters the vaginal microbiota and microenvironment in a Kenyan sex worker cohort and is also associated with increased susceptibility to HIV-1 in humanized mice. Disease Models & Mechanisms. 2019; 12 (10):dmm.039669.
Chicago/Turabian StyleJocelyn M. Wessels; Julie Lajoie; Maeve I. J. Hay Cooper; Kenneth Omollo; Allison M. Felker; Danielle Vitali; Haley A. Dupont; Philip V. Nguyen; Kristen Mueller; Fatemeh Vahedi; Joshua Kimani; Julius Oyugi; Juliana Cheruiyot; John N. Mungai; Alexandre Deshiere; Michel J. Tremblay; Tony Mazzulli; Jennifer C. Stearns; Ali A. Ashkar; Keith R. Fowke; Michael G. Surette; Charu Kaushic. 2019. "Medroxyprogesterone acetate alters the vaginal microbiota and microenvironment in a Kenyan sex worker cohort and is also associated with increased susceptibility to HIV-1 in humanized mice." Disease Models & Mechanisms 12, no. 10: dmm.039669.
The hormonal contraceptive Medroxyprogesterone Acetate (MPA) is associated with increased risk of Human Immunodeficiency Virus (HIV), via incompletely understood mechanisms. Increased diversity in the vaginal microbiota modulates genital inflammation and is associated with increased HIV-1 acquisition. However, the effect of MPA on diversity of the vaginal microbiota is relatively unknown. In a cohort of female Kenyan sex workers, negative for sexually transmitted infections (STIs), with Nugent Scores
Jocelyn M. Wessels; Julie Lajoie; Maeve I. J. Hay Cooper; Kenneth Omollo; Allison M. Felker; Danielle Vitali; Haley A. Dupont; Philip V. Nguyen; Kristen Mueller; Fatemeh Vahedi; Joshua Kimani; Julius Oyugi; Juliana Cheruiyot; John N. Mungai; Alexandre Deshiere; Michel J. Tremblay; Tony Mazzulli; Jennifer C. Stearns; Ali A. Ashkar; Keith R. Fowke; Michael G. Surette; Charu Kaushic; Kennenth Omollo. Medroxyprogesterone acetate mediated alteration in the vaginal microbiota and microenvironment in a Kenyan sex worker cohort. 2018, 483180 .
AMA StyleJocelyn M. Wessels, Julie Lajoie, Maeve I. J. Hay Cooper, Kenneth Omollo, Allison M. Felker, Danielle Vitali, Haley A. Dupont, Philip V. Nguyen, Kristen Mueller, Fatemeh Vahedi, Joshua Kimani, Julius Oyugi, Juliana Cheruiyot, John N. Mungai, Alexandre Deshiere, Michel J. Tremblay, Tony Mazzulli, Jennifer C. Stearns, Ali A. Ashkar, Keith R. Fowke, Michael G. Surette, Charu Kaushic, Kennenth Omollo. Medroxyprogesterone acetate mediated alteration in the vaginal microbiota and microenvironment in a Kenyan sex worker cohort. . 2018; ():483180.
Chicago/Turabian StyleJocelyn M. Wessels; Julie Lajoie; Maeve I. J. Hay Cooper; Kenneth Omollo; Allison M. Felker; Danielle Vitali; Haley A. Dupont; Philip V. Nguyen; Kristen Mueller; Fatemeh Vahedi; Joshua Kimani; Julius Oyugi; Juliana Cheruiyot; John N. Mungai; Alexandre Deshiere; Michel J. Tremblay; Tony Mazzulli; Jennifer C. Stearns; Ali A. Ashkar; Keith R. Fowke; Michael G. Surette; Charu Kaushic; Kennenth Omollo. 2018. "Medroxyprogesterone acetate mediated alteration in the vaginal microbiota and microenvironment in a Kenyan sex worker cohort." , no. : 483180.
BV treatment reduced genital CD4+ T-cell HIV susceptibility and IL-1 levels, but dramatically increased the genital chemokines that may enhance HIV susceptibility; the latter effect was related to the restoration of an Lactobacillus iners-dominated microbiota. Further studies are needed before treatment of asymptomatic BV can be recommended for HIV prevention in ACB communities.
Vineet Joag; Onyango Obila; Pawel Gajer; Milcah Carol Scott; Sara Dizzell; Michael Humphrys; Kamnoosh Shahabi; Sanja Huibner; Brett Shannon; Wangari Tharao; Marianne Mureithi; Julius Oyugi; Joshua Kimani; Charu Kaushic; Jacques Ravel; Omu Anzala; Rupert Kaul. Impact of Standard Bacterial Vaginosis Treatment on the Genital Microbiota, Immune Milieu, and Ex Vivo Human Immunodeficiency Virus Susceptibility. Clinical Infectious Diseases 2018, 68, 1675 -1683.
AMA StyleVineet Joag, Onyango Obila, Pawel Gajer, Milcah Carol Scott, Sara Dizzell, Michael Humphrys, Kamnoosh Shahabi, Sanja Huibner, Brett Shannon, Wangari Tharao, Marianne Mureithi, Julius Oyugi, Joshua Kimani, Charu Kaushic, Jacques Ravel, Omu Anzala, Rupert Kaul. Impact of Standard Bacterial Vaginosis Treatment on the Genital Microbiota, Immune Milieu, and Ex Vivo Human Immunodeficiency Virus Susceptibility. Clinical Infectious Diseases. 2018; 68 (10):1675-1683.
Chicago/Turabian StyleVineet Joag; Onyango Obila; Pawel Gajer; Milcah Carol Scott; Sara Dizzell; Michael Humphrys; Kamnoosh Shahabi; Sanja Huibner; Brett Shannon; Wangari Tharao; Marianne Mureithi; Julius Oyugi; Joshua Kimani; Charu Kaushic; Jacques Ravel; Omu Anzala; Rupert Kaul. 2018. "Impact of Standard Bacterial Vaginosis Treatment on the Genital Microbiota, Immune Milieu, and Ex Vivo Human Immunodeficiency Virus Susceptibility." Clinical Infectious Diseases 68, no. 10: 1675-1683.
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.
Jocelyn M. Wessels; Allison M. Felker; Haley A. Dupont; Charu Kaushic. The relationship between sex hormones, the vaginal microbiome and immunity in HIV-1 susceptibility in women. Disease Models & Mechanisms 2018, 11, 1 .
AMA StyleJocelyn M. Wessels, Allison M. Felker, Haley A. Dupont, Charu Kaushic. The relationship between sex hormones, the vaginal microbiome and immunity in HIV-1 susceptibility in women. Disease Models & Mechanisms. 2018; 11 (9):1.
Chicago/Turabian StyleJocelyn M. Wessels; Allison M. Felker; Haley A. Dupont; Charu Kaushic. 2018. "The relationship between sex hormones, the vaginal microbiome and immunity in HIV-1 susceptibility in women." Disease Models & Mechanisms 11, no. 9: 1.
Charu Kaushic. Special issue on “omics data in reproductive immunology”. American Journal of Reproductive Immunology 2018, 80, e13025 .
AMA StyleCharu Kaushic. Special issue on “omics data in reproductive immunology”. American Journal of Reproductive Immunology. 2018; 80 (2):e13025.
Chicago/Turabian StyleCharu Kaushic. 2018. "Special issue on “omics data in reproductive immunology”." American Journal of Reproductive Immunology 80, no. 2: e13025.
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.
Haley A. Dupont; Jeff Lam; Matthew W. Woods; Mohammed A. Zahoor; Charu Kaushic. Hormonal influence on HIV-1 transmission in the female genital tract: New insights from systems biology. American Journal of Reproductive Immunology 2018, 80, e13019 .
AMA StyleHaley A. Dupont, Jeff Lam, Matthew W. Woods, Mohammed A. Zahoor, Charu Kaushic. Hormonal influence on HIV-1 transmission in the female genital tract: New insights from systems biology. American Journal of Reproductive Immunology. 2018; 80 (2):e13019.
Chicago/Turabian StyleHaley A. Dupont; Jeff Lam; Matthew W. Woods; Mohammed A. Zahoor; Charu Kaushic. 2018. "Hormonal influence on HIV-1 transmission in the female genital tract: New insights from systems biology." American Journal of Reproductive Immunology 80, no. 2: e13019.
More than 40% of HIV infections occur via female reproductive tract (FRT) through heterosexual transmission. Epithelial cells that line the female genital mucosa are the first line of defense against HIV-1 and other sexually transmitted pathogens. These sentient cells recognize and respond to external stimuli by induction of a range of carefully balanced innate immune responses. Previously, we have shown that in response to HIV-1 gp120, the genital epithelial cells (GECs) from upper reproductive tract induce an inflammatory response that may facilitate HIV-1 translocation and infection. In this study, we report that the endometrial and endocervical GECs simultaneously induce biologically active interferon-β (IFNβ) antiviral responses following exposure to HIV-1 that act to protect the epithelial tight junction barrier. The innate antiviral response was directly induced by HIV-1 envelope glycoprotein gp120 and addition of gp120 neutralizing antibody inhibited IFNβ production. Interferon-β was induced by gp120 in upper GECs through Toll-like receptor 2 signaling and required presence of heparan sulfate on epithelial cell surface. The induction of IFNβ was dependent upon activation of transcription factor IRF3 (interferon regulatory factor 3). The IFNβ was biologically active, had a protective effect on epithelial tight junction barrier and was able to inhibit HIV-1 infection in TZM-bl indicator cells and HIV-1 replication in T cells. This is the first report that recognition of HIV-1 by upper GECs leads to induction of innate antiviral pathways. This could explain the overall low infectivity of HIV-1 in the FRT and could be exploited for HIV-1 prophylaxis.
Aisha Nazli; Sara Dizzell; Muhammad Atif Zahoor; Victor H Ferreira; Jessica Kafka; Matthew William Woods; Michel Ouellet; Ali A Ashkar; Michel J Tremblay; Dawn Me Bowdish; Charu Kaushic. Interferon-β induced in female genital epithelium by HIV-1 glycoprotein 120 via Toll-like-receptor 2 pathway acts to protect the mucosal barrier. Cellular & Molecular Immunology 2018, 16, 178 -194.
AMA StyleAisha Nazli, Sara Dizzell, Muhammad Atif Zahoor, Victor H Ferreira, Jessica Kafka, Matthew William Woods, Michel Ouellet, Ali A Ashkar, Michel J Tremblay, Dawn Me Bowdish, Charu Kaushic. Interferon-β induced in female genital epithelium by HIV-1 glycoprotein 120 via Toll-like-receptor 2 pathway acts to protect the mucosal barrier. Cellular & Molecular Immunology. 2018; 16 (2):178-194.
Chicago/Turabian StyleAisha Nazli; Sara Dizzell; Muhammad Atif Zahoor; Victor H Ferreira; Jessica Kafka; Matthew William Woods; Michel Ouellet; Ali A Ashkar; Michel J Tremblay; Dawn Me Bowdish; Charu Kaushic. 2018. "Interferon-β induced in female genital epithelium by HIV-1 glycoprotein 120 via Toll-like-receptor 2 pathway acts to protect the mucosal barrier." Cellular & Molecular Immunology 16, no. 2: 178-194.
Genital epithelial cells (GECs) line the mucosal surface of the female genital tract (FGT) and are the first cells that interface with both commensal microbiota and sexually transmitted pathogens. Despite the protective barrier formed by GECs, the FGT is a major site of HIV-1 infection. This highlights the importance of studying the interaction of HIV-1 and GECs. Using microarray analysis, we characterized the transcriptional profile of primary endometrial GECs grown in the presence or absence of physiological levels of E2 (10−9 mol/L) or P4 (10−7 mol/L) following acute exposure to HIV-1 for 6 hours. Acute exposure of primary endometrial GECs to HIV-1 resulted in the expression of genes related to inflammation, plasminogen activation, adhesion and diapedesis and interferon response. Interestingly, exposure to HIV-1 in the presence of E2 and P4 resulted in differential transcriptional profiles, suggesting that the response of primary endometrial GECs to HIV-1 exposure is modulated by female sex hormones. The gene expression signature of endometrial GECs indicates that the response of these cells may be key to determining host susceptibility to HIV-1 and that sex hormones modulate these interactions. This study allows us to explore possible mechanisms that explain the hormone-mediated fluctuation of HIV-1 susceptibility in women.
Muhammad Atif Zahoor; Matthew William Woods; Sara Dizzell; Aisha Nazli; Kristen M. Mueller; Philip V. Nguyen; Chris P. Verschoor; Charu Kaushic. Transcriptional profiling of primary endometrial epithelial cells following acute HIV-1 exposure reveals gene signatures related to innate immunity. American Journal of Reproductive Immunology 2018, 79, e12822 .
AMA StyleMuhammad Atif Zahoor, Matthew William Woods, Sara Dizzell, Aisha Nazli, Kristen M. Mueller, Philip V. Nguyen, Chris P. Verschoor, Charu Kaushic. Transcriptional profiling of primary endometrial epithelial cells following acute HIV-1 exposure reveals gene signatures related to innate immunity. American Journal of Reproductive Immunology. 2018; 79 (4):e12822.
Chicago/Turabian StyleMuhammad Atif Zahoor; Matthew William Woods; Sara Dizzell; Aisha Nazli; Kristen M. Mueller; Philip V. Nguyen; Chris P. Verschoor; Charu Kaushic. 2018. "Transcriptional profiling of primary endometrial epithelial cells following acute HIV-1 exposure reveals gene signatures related to innate immunity." American Journal of Reproductive Immunology 79, no. 4: e12822.
Mycobacterium tuberculosis, the pathogen causing pulmonary tuberculosis (TB) in humans, has evolved to delay Th1 immunity in the lung. Although conventional dendritic cells (cDCs) are known to be critical to the initiation of T cell immunity, the differential roles and molecular mechanisms of migratory CD11b+ and CD103+ cDC subsets in anti–M. tuberculosis Th1 activation remain unclear. Using a murine model of pulmonary M. tuberculosis infection, we found that slow arrival of M. tuberculosis–bearing migratory CD11b+ and CD103+ cDCs at the draining lymph nodes preceded the much-delayed Th1 immunity and protection in the lung. Contrary to their previously described general roles in Th polarization, CD11b+ cDCs, but not CD103+ cDCs, were critically required for Th1 activation in draining lymph nodes following M. tuberculosis infection. CD103+ cDCs counterregulated CD11b+ cDC–mediated Th1 activation directly by producing the immune-suppressive cytokine IL-10. Thus, our study provides new mechanistic insights into differential Th immune regulation by migratory cDC subsets and helps to develop novel vaccines and therapies.
Rocky Lai; Mangalakumari Jeyanathan; Sam Afkhami; Anna Zganiacz; Joanne A. Hammill; Yushi Yao; Charu Kaushic; Zhou Xing. CD11b+Dendritic Cell–Mediated Anti–Mycobacterium tuberculosisTh1 Activation Is Counterregulated by CD103+Dendritic Cells via IL-10. The Journal of Immunology 2018, 200, ji1701109 -1760.
AMA StyleRocky Lai, Mangalakumari Jeyanathan, Sam Afkhami, Anna Zganiacz, Joanne A. Hammill, Yushi Yao, Charu Kaushic, Zhou Xing. CD11b+Dendritic Cell–Mediated Anti–Mycobacterium tuberculosisTh1 Activation Is Counterregulated by CD103+Dendritic Cells via IL-10. The Journal of Immunology. 2018; 200 (5):ji1701109-1760.
Chicago/Turabian StyleRocky Lai; Mangalakumari Jeyanathan; Sam Afkhami; Anna Zganiacz; Joanne A. Hammill; Yushi Yao; Charu Kaushic; Zhou Xing. 2018. "CD11b+Dendritic Cell–Mediated Anti–Mycobacterium tuberculosisTh1 Activation Is Counterregulated by CD103+Dendritic Cells via IL-10." The Journal of Immunology 200, no. 5: ji1701109-1760.
It is well established that interferon gamma (IFN-γ) production by CD4 + T cells is critical for antiviral immunity against herpes simplex virus 2 (HSV-2) genital infection. However, the role of interleukin-17A (IL-17A) production by CD4 + T cells in HSV-2 antiviral immunity is yet to be elucidated. Here we demonstrate that IL-17A plays an important role in enhancing antiviral T helper type 1 (T h 1) responses in the female genital tract (FGT) and is essential for effective protection conferred by HSV-2 vaccination. While IL-17A did not play a critical role during primary genital HSV-2 infection, seen by lack of differences in susceptibility between IL-17A-deficient ( IL-17A −/− ) and wild-type (WT) C57BL/6 mice, it was critical for mediating antiviral responses after challenge/reexposure. Compared to WT mice, IL-17A −/− mice (i) infected intravaginally and reexposed or (ii) vaccinated intranasally and challenged intravaginally demonstrated poor outcomes. Following intravaginal HSV-2 reexposure or challenge, vaccinated IL-17A −/− mice had significantly higher mortality, greater disease severity, higher viral shedding, and higher levels of proinflammatory cytokines and chemokines in vaginal secretions. Furthermore, IL-17A −/− mice had impaired T h 1 cell responses after challenge/reexposure, with significantly lower proportions of vaginal IFN-γ + CD4 + T cells. The impaired T h 1 cell responses in IL-17A −/− mice coincided with smaller populations of IFN-γ + CD4 + tissue resident memory T (T RM ) cells in the genital tract postimmunization. Taken together, these findings describe a novel role for IL-17A in regulating antiviral IFN-γ + T h 1 cell immunity in the vaginal tract. This strategy could be exploited to enhance antiviral immunity following HSV-2 vaccination. IMPORTANCE T helper type 1 (T h 1) immunity, specifically interferon gamma (IFN-γ) production by CD4 + T cells, is critical for protection against genital herpesvirus (HSV-2) infection, and enhancing this response can potentially help improve disease outcomes. Our study demonstrated that interleukin-17A (IL-17A) plays an essential role in enhancing antiviral T h 1 responses in the female genital tract (FGT). We found that in the absence of IL-17A, preexposed and vaccinated mice showed poor disease outcomes and were unable to overcome HSV-2 reexposure/challenge. IL-17A-deficient mice ( IL-17A −/− ) had smaller populations of IFN-γ + CD4 + tissue resident memory T (T RM ) cells in the genital tract postimmunization than did wild-type (WT) mice, which coincided with attenuated T h 1 responses postchallenge. This has important implications for developing effective vaccines against HSV-2, as we propose that strategies inducing IL-17A in the genital tract may promote more effective T h 1 cell immunity and better overall protection.
Puja Bagri; Varun C. Anipindi; Philip V. Nguyen; Danielle Vitali; Martin Stampfli; Charu Kaushic. Novel Role for Interleukin-17 in Enhancing Type 1 Helper T Cell Immunity in the Female Genital Tract following Mucosal Herpes Simplex Virus 2 Vaccination. Journal of Virology 2017, 91, e01234-17 .
AMA StylePuja Bagri, Varun C. Anipindi, Philip V. Nguyen, Danielle Vitali, Martin Stampfli, Charu Kaushic. Novel Role for Interleukin-17 in Enhancing Type 1 Helper T Cell Immunity in the Female Genital Tract following Mucosal Herpes Simplex Virus 2 Vaccination. Journal of Virology. 2017; 91 (23):e01234-17.
Chicago/Turabian StylePuja Bagri; Varun C. Anipindi; Philip V. Nguyen; Danielle Vitali; Martin Stampfli; Charu Kaushic. 2017. "Novel Role for Interleukin-17 in Enhancing Type 1 Helper T Cell Immunity in the Female Genital Tract following Mucosal Herpes Simplex Virus 2 Vaccination." Journal of Virology 91, no. 23: e01234-17.
Approximately 40% of HIV-1 infections occur in the female genital tract (FGT), primarily through heterosexual transmission. FGT factors determining outcome of HIV-1 exposure are incompletely understood, limiting prevention strategies. Here, humanized NOD-Rag1−/− γc−/− mice differentially reconstituted with human CD34+ -enriched hematopoietic stem cells (Hu-mice), were used to assess target cell frequency and viral inoculation dose as determinants of HIV-1 infection following intravaginal (IVAG) challenge. Results revealed a significant correlation between HIV-1 susceptibility and hCD45+ target cells in the blood, which correlated with presence of target cells in the FGT, in the absence of local inflammation. HIV-1 plasma load was associated with viral dose at inoculation and frequency of target cells. Events following IVAG HIV-1 infection; viral dissemination and CD4 depletion, were not affected by these parameters. Following IVAG inoculation, HIV-1 titres peaked, then declined in vaginal lavage while plasma showed a reciprocal pattern. The greatest frequency of HIV-1-infected (p24+) cells were found one week post-infection in the FGT versus blood and spleen, suggesting local viral amplification. Five weeks post-infection, HIV-1 disseminated into systemic tissues, in a dose-dependent manner, followed by depletion of hCD45+ CD3+ CD4+ cells. Results indicate target cell frequency in the Hu-mouse FGT is a key determinant of HIV-1 infection, which might provide a useful target for prophylaxis in women.
Philip V. Nguyen; Jocelyn M. Wessels; Kristen Mueller; Fatemeh Vahedi; Varun Anipindi; Chris P. Verschoor; Marianne Chew; Alexandre Deshiere; Uladzimir Karniychuk; Tony Mazzulli; Michel J. Tremblay; Ali A. Ashkar; Charu Kaushic. Frequency of Human CD45+ Target Cells is a Key Determinant of Intravaginal HIV-1 Infection in Humanized Mice. Scientific Reports 2017, 7, 1 -15.
AMA StylePhilip V. Nguyen, Jocelyn M. Wessels, Kristen Mueller, Fatemeh Vahedi, Varun Anipindi, Chris P. Verschoor, Marianne Chew, Alexandre Deshiere, Uladzimir Karniychuk, Tony Mazzulli, Michel J. Tremblay, Ali A. Ashkar, Charu Kaushic. Frequency of Human CD45+ Target Cells is a Key Determinant of Intravaginal HIV-1 Infection in Humanized Mice. Scientific Reports. 2017; 7 (1):1-15.
Chicago/Turabian StylePhilip V. Nguyen; Jocelyn M. Wessels; Kristen Mueller; Fatemeh Vahedi; Varun Anipindi; Chris P. Verschoor; Marianne Chew; Alexandre Deshiere; Uladzimir Karniychuk; Tony Mazzulli; Michel J. Tremblay; Ali A. Ashkar; Charu Kaushic. 2017. "Frequency of Human CD45+ Target Cells is a Key Determinant of Intravaginal HIV-1 Infection in Humanized Mice." Scientific Reports 7, no. 1: 1-15.
Medroxyprogesterone acetate (MPA), a progestin-based hormonal contraceptive designed to mimic progesterone, has been linked to increased human immunodeficiency virus (HIV-1) susceptibility. Genital epithelial cells (GECs) form the mucosal lining of the female genital tract (FGT) and provide the first line of protection against HIV-1. The impact of endogenous sex hormones or MPA on the gene expression profile of GECs has not been comprehensively documented. Using microarray analysis, we characterized the transcriptional profile of primary endometrial epithelial cells grown in physiological levels of E2, P4, and MPA. Each hormone treatment altered the gene expression profile of GECs in a unique manner. Interestingly, although MPA is a progestogen, the gene expression profile induced by it was distinct from P4. MPA increased gene expression of genes related to inflammation and cholesterol synthesis linked to innate immunity and HIV-1 susceptibility. The analysis of gene expression profiles provides insights into the effects of sex hormones and MPA on GECs and allows us to posit possible mechanisms of the MPA-mediated increase in HIV-1 acquisition.
Matthew W. Woods; Muhammad Atif Zahoor; Sara Dizzell; Chris P. Verschoor; Charu Kaushic. Medroxyprogesterone acetate-treated human, primary endometrial epithelial cells reveal unique gene expression signature linked to innate immunity and HIV-1 susceptibility. American Journal of Reproductive Immunology 2017, 79, e12781 .
AMA StyleMatthew W. Woods, Muhammad Atif Zahoor, Sara Dizzell, Chris P. Verschoor, Charu Kaushic. Medroxyprogesterone acetate-treated human, primary endometrial epithelial cells reveal unique gene expression signature linked to innate immunity and HIV-1 susceptibility. American Journal of Reproductive Immunology. 2017; 79 (1):e12781.
Chicago/Turabian StyleMatthew W. Woods; Muhammad Atif Zahoor; Sara Dizzell; Chris P. Verschoor; Charu Kaushic. 2017. "Medroxyprogesterone acetate-treated human, primary endometrial epithelial cells reveal unique gene expression signature linked to innate immunity and HIV-1 susceptibility." American Journal of Reproductive Immunology 79, no. 1: e12781.