Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA390661 | ENA |
REPOSITORIES: ENA
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Project description:There is an ongoing debate whether sex hormones impact risk of HIV transmission. This study evaluated if serum estradiol (E2) and progesterone (P4) levels predict the ex vivo cervical tissue HIV infection, tissue immune environment and transcriptome. Cervical mucosa and peripheral blood samples were collected from subjects undergoing total hysterectomies. Tissue explants were challenged with HIV-1BaL and infection was monitored in the supernatants by HIV gag qRT-PCR. Serum E2 and P4 concentrations were measured by radioimmunoassay. Blood and tissue T cell phenotypes were characterized by flow cytometry. Tissue responses to HIV exposure were measured by Luminex. Tissue transcriptome in an unchallenged portion of mucosa was analyzed by RNAseq. We show that serum E2 concentrations inversely associated with cervical HIV-1BaL infection ex vivo and this association was independent of potential confounders (race, age, phase of the cycle, parakeratosis, metaplasia, histopathological signs of cervical inflammation, and HSV-2 status). E2 concentrations did not associate with T cell frequencies/phenotype in either tissues or blood. However, higher E2 concentrations predicted a mixed profile of pro-/anti-inflammatory genes expression and HIV-induced soluble mediators. In contrast, P4 concentrations or P4/E2 ratios did not associate with ex vivo tissue infection level, but increased P4 concentrations associated with high frequencies of a4b7+ and low LFA-1+ T cells and mainly pro-inflammatory responses to HIV. These data suggest inhibitory effect of E2 on local mucosal HIV amplification early post transmission, provide insights in the mechanism of E2-mediated anti-HIV activity and highlight P4-associated immune changes in the mucosa.
2020-06-15 | GSE100094 | GEO
Project description:The rectal mucosa is a critical site of HIV vulnerability. We sought to identify transcriptomic features of rectal mucosal tissue prior to exposure associated with support or restriction of HIV replication. For the first time, we identified rectal tissue transcriptomic signatures associated with increased p24 production utilizing an ex-vivo model. Our findings are highly relevant to HIV transmission and the early establishment of HIV reservoirs in humans.
2022-08-26 | GSE211922 | GEO
Project description:Highly Exposed-Seronegatives (HESN) individuals do not contract HIV-1 infection despite long-term exposure; few comprehensive studies examining behavior, mucosal tissue, and peripheral immune parameters in sexually-exposed HESN have been completed. To this end, we assessed rate of condomless vaginal sex, the immune activation status (peripheral blood) and gene expression (ectocervical biopsies) in female cohort of high-risk female sex workers [FSW] (n=50) and non-sex worker women [CG] (n=32) in San Juan, Puerto Rico, USA. Of the 50 FSWs examined only 5 had detectable anti-HIV responses by either HIV gag-specific CD8+ T-Cell responses or mucosal anti-HIV envelope IgG/IgA. FSW had a uniform lower CD38 expression on circulating CD4+ or CD8+ T-Cells (both: p<0.0001:Wilcoxon Rank Sum). Cervical tissue from FSWs had greater levels of CD4+ T-Cell (p=0.040), CD123+ plasmacytoid Dendritic Cells (p=0.013) and CD68+ macrophage infiltrates (p=0.038). Cervical gene expression by RNA microarray indicated that FSW had a gene signature characterized by lower expression of genes associated with leukocyte homing and chemotaxis; partial interferon regulated gene signature; and lower gene expression of genes required for HIV infection such as CD4 and NUP153 indicating a lower mucosal immune activation state and reduced susceptibility to HIV-1 infection within mucosal tissue. Notably, Interferon (IFN)-ε expression was higher in FSW than CG women, as detected by RNA (microarray) and protein (IHC) expression in cervical epithelium. The observed levels of IFNε were associated with the reported frequency of unprotected intercourse. Finally, IFNε was induced by treatment of the ECT1 cell line with seminal fluid, suggesting that semen exposure may contribute to long-term protection. Decreased levels of immune activation and gene expression required for HIV infection along with semen-induced epithelial Interferon ε production within the reproductive tract of FSWs highlight distinct host intrinsic resistance mechanisms that may contribute to long-term HIV seronegative status in spite of high-risk condomless sex.
2019-11-21 | GSE63441 | GEO
Project description:A comparison of rectal mucosal RNA transcriptome findings between transgender women using feminizing hormone therapy, men who have sex with men engaging in receptive anal intercourse, and males who had never engaged in anal intercourse demonstrates differential gene expression involving pathways critical for mucosal inflammation, suggesting the urgent need for further exploration into the immunologic effects of cross-sex hormone therapy in the rectal mucosa and the potential impact on HIV transmission risk at this site.
2023-03-21 | GSE141785 | GEO
Project description:Schistosomiasis increases the risk of HIV acquisition in women, by mechanisms that are incompletely defined. Our objective was to determine how the cervical environment is impacted by Schistosoma haematobium or S. mansoni infection using mucosal gene expression and cervicovaginal lavage cytokine levels. We recruited women with/without S. haematobium and with/without S. mansoni infections from separate villages in rural Tanzania, as determined by urine and stool microscopy and serum circulating anodic antigen. RNA was extracted from cervical cytobrush samples for transcriptome analysis. Cytokine levels were measured by magnetic bead immunoassay. In the S. haematobium village, 110 genes were differentially expressed in the cervical mucosa of women with (n=18) versus without (n=39) S. haematobium. Among the 27 cytokines analyzed in cervicovaginal lavage fluids, interleukin 15 (IL-15) was lower in women with S. haematobium (62.8 versus 102.9 pg/mL, adjusted p=0.0013). Differences were not observed in the S. mansoni setting between women with (n=11) or without (n=29) S. mansoni. We demonstrate altered cervical mucosal gene expression and lower IL-15 levels in women with S. haematobium but not S. mansoni, which may impact HIV acquisition and cancer risks. Studies to determine effects of anti-schistosome treatment on these mucosal alterations are needed.
2019-12-21 | GSE142456 | GEO
Project description:Immunological correlates of natural resistance to HIV have been identified in HIV-exposed seronegative (HESN) individuals. The cervicovaginal epithelium has not been studied for such correlates despite constituting an important barrier against sexual HIV transmission. To fill this gap in knowledge, we collected samples of blood and genital mucosa from Kenyan HESN sex workers (n=29) and controls (n=33). The samples were analyzed by several methods including tissue-based RNA sequencing. A significantly higher relative proportion of regulatory T cells and lower proportion of activated cervical T cells were found in the HESN group compared with the controls. However, they had comparable tissue RNA transcriptional profiles. In conclusion, the identification of an increased proportion of regulatory T cells in blood, a lower proportion of activated cervical T cells, and an intact ectocervical microenvironment in HESN individuals add new data to current knowledge about natural resistance to sexual transmission of HIV.
2021-04-20 | GSE165132 | GEO
Project description:Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity is restricting viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with SIVmac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by mRNA deep sequencing (mRNA-seq) at 3 and 12 days post inoculation (DPI) in 4 animals for each time point.
2014-04-17 | GSE56845 | GEO
Project description:Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity is restricting viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with SIVmac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by mRNA deep sequencing (mRNA-seq) at 3 and 12 days post inoculation (DPI) in 4 animals for each time point. The eight RMs were intrarectally challenged with SIVmac251 using 1 mL of a high-dose inoculum (6000 TCID50/mL). SIV inoculates were deposited at a rectal depth of 25 mm from the anus. Baseline rectal samples were obtained 14 days prior to viral challenge by pinch biopsy.
2014-04-17 | E-GEOD-56845 | biostudies-arrayexpress
Project description:Modulation of mucus production by the human endo- and ecto-cervical epithelium by steroid hormones and associated interactions with commensal microbiome play a central role in the physiology and pathophysiology of the female reproductive tract. However, most of our knowledge about these interactions is based on results from animal studies or in vitro models that fail to faithfully mimic the mucosal environment of the human cervix. Here we describe microfluidic organ-on-a-chip (Organ Chip) models of the human cervical mucosa that recreate the cervical epithelial-stromal interface with a functional epithelial barrier and produce abundant mucus that has compositional, biophysical, and hormone-responsive properties similar to the living cervix. Application of continuous fluid flow to chips lined primary human cervical epithelial cells from a commercial source that contained a mixture of primary human ecto- and endo-cervical epithelial cells promoted preferential expression of the ecto-cervical phenotype, whereas use of periodic flow including periods of stasis induced endo-cervical specialization. When the periodic flow Cervix Chips were co-cultured with living Lactobacillus crispatus and Gardnerella vaginalis bacterial communities to respectively mimic the effects of human host interactions with optimal (healthy) or non-optimal (dysbiotic) microbiome associated with an ascending infection in the female reproductive tract, significant differences in tissue innate immune responses, barrier function, cell viability and protein profile, and mucus composition were detected reminiscent of those observed in vivo. Thus, these Organ Chip models of human cervix provide a physiologically relevant experimental in vitro model to study cervical mucus physiology and its role in human host-microbiome interactions as well as a potential preclinical testbed for development of therapeutic interventions to enhance women's health.
2023-12-11 | MSV000093636 | MassIVE
Project description:HIV-1 infections of women are mainly acquired through female reproductive tract where cervical and vaginal epithelial cells are the first line of defense. Although HIV-1 does not directly infect epithelial cells, HIV-1 obligatorily interacts with and crosses over epithelial layer to infect susceptible target cells, mainly CD4+ T cells, in the lamina propria to initiate an infection. However, the mechanism and ramification of the interaction of HIV-1 and epithelial cells in vaginal transmission of HIV-1 remain to be elucidated. We hypothesized that cervical epithelial cells are not a passive barrier, but actively respond to HIV-1 to change mucosal milieu and facilitate HIV-1 transmission. We tested this hypothesis by studying the responses of cervical epithelial cells to HIV-1 through profiling genome-wide transcription. We found 1) cervical epithelial cells actively respond to HIV-1. Five hundred forty-three transcripts/genes in cervical epithelial cells were significantly altered in expression at four hours post exposure to HIV-1, of which many relate to important signaling pathways, such as innate immune responses, pattern recognition receptors, apoptosis, biosynthesis, and energy production, 2) HIV-1 increases the expression of CXC Chemokines (IL-8, CXCL1 and CXCL3) in cervical epithelial cells. IL-8 and CXCL1 are potent chemotactic for multinuclear neutrophils (MNP), monocytes and a minority of lymphocytes, and CXCL3 is predominant chemotactic for monocytes, 3) HIV-1 increases the expression of key inflammatory enzymes-COX-1 and COX-2. COX-1 is responsible for the production of prostaglandins that are important for homeostatic functions, and COX-2 is a key enzyme to convert arachidonic acid to prostaglandins, key inflammatory mediators, and 4) the increased expression of IL-8 and COX-2 revealed using microarray analysis was mapped into the endocervical epithelial cells of macaques inoculated with inactivated SIV in vivo. Our date lead to a role model of epithelial cells in HIV-1 vaginal transmission, that is the axis of HIV-1, epithelial cells, proinflammatory molecules (IL-8, CXCL1, CXCL3, COX-1 and COX-2), cell recruitment (MNP, monocytes and T cells), and inflammation. This model implies that moderating epithelial proinflammatory response to HIV-1 may be utilized in prevention of HIV vaginal transmission. Human endocervical epithelial cell line, CRL-2615, was inoculated with HIV-1 ME1 and collected 4hrs post exposure. Biologically duplicated mRNAs were prepared after exposure.
2013-02-01 | E-GEOD-42291 | biostudies-arrayexpress