MicroRNA profiling of Basal ganglia tissue from chronically SIV infected rhesus macaques II
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ABSTRACT:
ORGANISM(S): Homo sapiens Macaca mulatta
PROVIDER: GSE220709 | GEO | 2023/02/28
REPOSITORIES: GEO
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Project description:The study describes miRNA expression in Gingival tissue of chronically SIV-infected rhesus macaques. HIV/SIV-associated periodontal disease (gingivitis/periodontitis) (PD) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Employing a systems biology approach, we report molecular changes underlying PD and its modulation by phytocannabinoids [delta-9-tetrahydrocannabinol (9-THC)] in uninfected and SIV-infected rhesus macaques (RMs) untreated (VEH-untreated/SIV) or treated with vehicle (VEH/SIV) or 9-THC (THC/SIV). VEH- untreated/SIV but not THC/SIV RMs showed significant enrichment of genes linked to anti-viral defense, interferon-beta, NFkB, RIG-1, and JAK-STAT signaling. We focused on the anti-microbial DUOX1 and immune activation marker IDO1 that were reciprocally regulated in gingiva of VEH-untreated/SIV RMs. Both proteins localized to the gingival epithelium and CD163+ macrophages, and showed differential expression in the gingiva of THC/SIV and VEH/SIV RMs. Additionally, inflammation-associated miR-21, miR-142-3p, miR-223, and miR-125a-5p showed significantly higher expression in the gingiva of VEH/SIV RMs. In human primary gingival epithelial cells, miR-125a-5p post-transcriptionally downregulated DUOX1 These findings strongly support a role for differential miRNA expression associated with HIV/SIV induced gingival mucosal dysfunction.
2021-11-30 | GSE181541 | GEO
Project description:HIV/SIV-associated periodontal disease (gingivitis/periodontitis) (PD) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Employing a systems biology approach, we report molecular changes underlying PD and its modulation by phytocannabinoids [delta-9-tetrahydrocannabinol (THC)] in uninfected and SIV-infected rhesus macaques (RMs) treated with vehicle (VEH/SIV) or THC (THC/SIV). VEH/SIV but not THC/SIV RMs showed significant enrichment of genes linked to anti-viral defense, interferon-beta, NFkB, RIG-1, and JAK-STAT signaling. We focused on the anti-microbial DUOX1 and immune activation marker IDO1 that were reciprocally regulated in gingiva of VEH/SIV RMs. Both proteins localized to the gingival epithelium and CD163+ macrophages, and showed differential expression in the gingiva of THC/SIV and VEH/SIV RMs. Additionally, inflammation-associated miR-21, miR-142-3p, miR-223, and miR-125a-5p showed significantly higher expression in the gingiva of VEH/SIV RMs. In human primary gingival epithelial cells, miR-125a-5p post-transcriptionally downregulated DUOX1 and THC inhibited IDO1 protein expression through a cannabinoid receptor-2 mediated mechanism. Interestingly, THC/SIV RMs showed relatively reduced plasma levels of kynurenine, kynurenate, and the neurotoxic quinolinate compared to VEH/SIV RMs. Most importantly, THC blocked HIV/SIV-induced depletion of Firmicutes and Bacteroidetes, and reduced Gammaproteobacteria abundance in saliva. Reduced IDO1 protein expression was associated with significantly (p<0.05) higher abundance of Prevotella, Lactobacillus (L. salivarius, L. buchneri, L. fermentum, L. paracasei, L. rhamnosus, L. johnsonii) and Bifidobacteria and reduced abundance of the pathogenic Porphyromonas cangingivalis and Porphyromonas macacae. These translational findings suggest that phytocannabinoids could help reduce gingival/systemic inflammation and salivary dysbiosis in ART naïve and treated HIV individuals.
2021-11-30 | GSE181487 | GEO
Project description:The study describes miRNA expression in colon tissue following delta 9 tetrahydrocannabinol (Δ9-THC) administration to chronically SIV-infected rhesus macaques. To identify the underlying molecular mechanisms underlying its anti-inflammatory effects, we simultaneously profiled miRNA and mRNA expression in colon of chronically simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) administered either vehicle (VEH/SIV; n=9) or Δ9- tetrahydrocannabinol (THC; THC/SIV; n=8). Relative to controls, differentially expressed miRNAs were ~2 fold higher in VEH/SIV than THC/SIV RMs. Proinflammatory miR-130a, miR-222 and miR-29b, Lipopolysaccharide-responsive miR-146b-5p and SIV-induced miR-190b were significantly upregulated in VEH/SIV RMs. Compared to VEH/SIV RMs, 10 miRNAs were significantly upregulated in THC-SIV RMs, among which miR-204 was confirmed to directly target MMP8, an extracellular matrix-degrading collagenase that was significantly downregulated in THC/SIV RMs. Moreover, THC/SIV RMs failed to upregulate proinflammatory miR-21, miR-141 and miR-222 and alpha/beta defensins, suggesting attenuated intestinal inflammation. Further, THC/SIV RMs showed higher expression of tight junction proteins (occludin, claudin-3), anti-inflammatory MUC13, keratin-8 (stress protection), PROM1 (epithelial proliferation) and anti-HIV CCL5. Trichrome mason staining detected significant collagen deposition (fibrosis) in the paracortex and B cell follicular zones of axillary lymph nodes from all VEH/SIV but none of the THC/SIV RMs, thus demonstrating the ability of THC to prevent lymph node fibrosis, a serious irreversible consequence of HIV induced chronic inflammation. Furthermore, using flow cytometry, we showed that THC suppressed intestinal T cell proliferation/activation (Ki67/HLADR) and exhaustion (PD1) and increased the percentages of anti-inflammatory CD163+ macrophages. Finally, while THC did not affect CD4+ T cell levels, it significantly reduced CD8+ T cell percentages in blood at 150 and 180 days post SIV infection. These translational findings strongly support a role for differential miRNA/gene induction and T cell activation in THC-mediated suppression of intestinal inflammation in HIV/SIV and potentially other chronic inflammatory diseases of the intestine.
2019-01-01 | GSE121440 | GEO
Project description:HIV/SIV associated oral mucosal disease/dysfunction (HAOMD) (gingivitis/periodontitis/salivary adenitis) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Using a systems biology approach, we investigated molecular changes (mRNA/microRNA) underlying HAOMD and its modulation by phytocannabinoids [delta-9-tetrahydrocannabinol (Δ9-THC)] in uninfected (n=5) and SIV-infected rhesus macaques untreated (VEH-untreated/SIV; n=7) or treated with vehicle (VEH/SIV; n=3) or Δ9-THC (THC/SIV; n=3). Relative to controls fewer mRNAs were upregulated in THC/SIV compared to VEH-untreated/SIV macaques. Gene enrichment analysis showed differential enrichment of biological functions involved in anti-viral defense, Type-I interferon, Toll-like receptor, RIG-1 and IL1R signaling in VEH-untreated/SIV macaques. We focused on the anti-ER-stress anterior gradient-2 (AGR2), epithelial barrier protecting and anti-dysbiotic WAP Four-Disulfide Core Domain 2 (WFDC2), and glucocorticoid-induced anti-inflammatory TSC22D3 (TSC22-domain family member 3) that were significantly downregulated in OPM of VEH-untreated/SIV macaques. All three proteins localized to minor salivary gland acini and secretory ducts and showed enhanced and reduced expression in OPM of THC/SIV and VEH/SIV macaques, respectively. Additionally, inflammation associated miR-21, miR-142-3p and miR-29b showed significantly higher expression in OPM of VEH-untreated/SIV macaques. TSC22D3 was validated as a target of miR-29b. These preliminary translational findings suggest that phytocannabinoids may safely and effectively reduce oral inflammatory responses in HIV/SIV and other diseases.
2020-07-01 | GSE150723 | GEO
Project description:Cannabinoid administration before and after simian immunodeficiency virus (SIV)-inoculation ameliorated disease progression and decreased inflammation in male rhesus macaques. Δ9-tetrahydrocannabinol (Δ9-THC) did not increase viral load in brain tissue or produce additive neuropsychological impairment in SIV-infected macaques. To determine if the neuroimmunomodulation of Δ9-THC involved differential microRNA (miR) expression, miR expression in the striatum of uninfected macaques receiving vehicle (VEH) or Δ9-THC (THC) and SIV-infected macaques administered either vehicle (VEH/SIV) or Δ9-THC (THC/SIV) was profiled using next generation deep sequencing.
2016-01-22 | GSE72766 | GEO
Project description:The study describes miRNA expression in Oropharyngeal tissue of chronically SIV-infected rhesus macaques. To identify the underlying molecular mechanisms we simultaneously profiled miRNA and mRNA expression in oropharyngeal tissues of chronically simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs). Relative to controls, we identified 48 (38-upregulated and 10 downregulated) differentially expressed (DE) miRNAs relative to uninfected controls (n=5). Interestingly, in terms of magnitude, miR-19a, miR-301, miR-142-3p, miR-32 and miR-142-5p were among a select list of miRNAs that showed the highest upregulation in OPM. An important finding is the significant upregulation in OPM of miR-21, a microRNA known to regulate periodontitis, T-cell activation and oral carcinoma. Interestingly, RNA-seq for gene expression profiling also confirmed miR-21 upregulation in OPM of VEH-untreated/SIV rhesus macaques. Using TargetScan 7.2, we identified TSC22D3 (TSC22-domain family member 3), an anti-inflammatory protein induced by glucocorticoids and IL10 that was significantly downregulated in OPM of VEH-untreated/SIV macaques to be a predicted target of miR-29b. TSC22D3 localized to minor salivary gland acini and secretory ducts and showed reduced expression in OPM of VEH-untreated chronically SIV macaques. Using luciferase reporter and overexpression assays, we confirmed TSC22D3 to be a direct target of miR-29b. Interestingly, expression of miR-150 was significantly downregulated, a miRNA we previously demonstrated to be downregulated during T cell activation in the intestine. These findings strongly support a role for differential miRNA expression associated with HIV/SIV induced oropharyngeal mucosal dysfunction.
2020-07-01 | GSE150662 | GEO
Project description:The study describes miRNA expression in intact duodenum following chronic delta 9 tetrahydrocannabinol (Δ9-THC) administration to SIV-infected rhesus macaques. Chronic Δ9-THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days post infection (DPI). At 60DPI, ~28% of miRNAs showed decreased expression in VEH/SIV compared to none in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149 and miR-187 previously shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator was confirmed as a direct miR-99b target. A significant increase in NOX4+ crypt epithelial cells was detected in VEH/SIV compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage.
2014-11-19 | GSE61654 | GEO
Project description:The study describes miRNA expression in intact duodenum following chronic delta 9 tetrahydrocannabinol (M-NM-^T9-THC) administration to SIV-infected rhesus macaques. Chronic M-NM-^T9-THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days post infection (DPI). At 60DPI, ~28% of miRNAs showed decreased expression in VEH/SIV compared to none in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149 and miR-187 previously shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator was confirmed as a direct miR-99b target. A significant increase in NOX4+ crypt epithelial cells was detected in VEH/SIV compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage. Twelve age and weight matched male Indian rhesus macaques were randomly divided into 4 groups. Group 1 (n=1) received vehicle (1:1:18 of emulphor : alcohol : saline) and no infection. Group 2 (THC only, n=3) animals received twice daily intramuscular injections of M-NM-^T9-THC and no infection. Group-3 THC/SIV, (n=4) animals received twice daily injections of vehicle and were infected intravenously with 100TCID50 of SIVmac251. Group-4 (VEH/SIV, n=4) animals received twice daily injections of M-NM-^T9-THC similar to group 1 for four weeks prior to SIV infection. Duodenal pinch biopsies were collected before infection and thereafter at 14 and 30 days post infection. All animals were necropsied at 60 days post SIV infection. ~100 ng of total RNA was first reverse transcribed and preamplified according to the manufacturerM-bM-^@M-^Ys recommendation. microRNA expression profiling was performed using TaqMan M-BM-.OpenArrayM-BM-. Human microRNA panels. Data analysis was performed using ExpressionSuiteM-BM-. software. Data was normalized to three endogenous controls (RNU44, RNU48 and snoU6). Delta CT values were calculated by subtracting individual miRNA CT values from an average of all three endogenous controls. Comparisons were made between preinfection and all three treatment groups at 14, 30 and 60 DPI. To determine the effect of chronic THC treatment during SIV infection, comparisons were also made between VEH/SIV and THC/SIV at all three time points.
2014-11-19 | E-GEOD-61654 | biostudies-arrayexpress
Project description:The dysregulation of the microbiota-gut-brain axis (MGBA) in people living with HIV (PLWH) consequent to gastrointestinal dysfunction (dysbiosis) can lead to neuroinflammation and persistent cognitive impairment, which underscores the need for new treatments. Here, we show that delta-9-tetrahydrocannabinol (THC) reduced neuroinflammation and microbiome alterations and enhanced plasma endocannabinoid, endocannabinoid-like and indole-3-propionate levels in chronically SIV-infected rhesus macaques. Long-term low-dose THC potently blocked expression of genes associated with type I interferon responses and excitotoxicity (SLC7A11) and enhanced protein expression of WFS1 (endoplasmic reticulum stress) and CRYM (oxidative stress) in basal ganglia. Additionally, THC successfully countered miR-142-3p mediated suppression of WFS1 via a CB1R mediated mechanism in HCN2 neuronal cells. Most importantly, THC increased the relative abundance of Firmicutes and Clostridia including IPA producersing C. botulinum, C. paraputrificum, C. cadaveris and butyrate producersing C. butyricum, Faecalibacterium prauzsnitzii and Butyricicoccus pullicaecorum in the colon. This study highlights low-dose THC as a potential disease-modifying agent that can positively modulate the MGBA by concurrently reducing neuroinflammation and promoting the growth of gut microbial species that produce neuroprotective metabolites like indole-3-propionate in PLWH HIV and other neurodegenerative diseases, thus meriting clinical trials.
2023-02-28 | GSE207518 | GEO
Project description:The study describes miRNA expression in colonic epithelium of chronic SIV-infected rhesus macaques. We profiled and characterized miRNA/mRNA expression exclusively in colonic epithelium (CE) of 12 chronically SIV-infected and 8 control rhesus macaques (RMs). About 46 miRNAs were differentially expressed (DE) (20-up and 26-down) in CE during chronic SIV infection. Using TargetScan, we bioinformatically crossed the predicted targets of DE miRNAs to genome-wide transcriptomic data and identified several critical miRNA-mRNA pairings that suggested miRNA-mediated regulation of aberrant epithelial gene expression in CE. Immunofluorescence, luciferase reporter and miRNA overexpression studies confirmed the ability of miR-130a and miR-212 to bind the 3’ UTR and downregulate protein expression of occludin (OCLN) and peroxisome proliferator activator receptor gamma (PPAR), respectively, two proteins with pivotal roles in epithelial barrier function. MiR-130a and miR-212 overexpression in Caco-2 cells significantly reduced transepithelial electrical resistance (TEER). Interestingly, delta-9-tetrahydrocannabinol (9-THC) treatment restored TEER to levels observed with control miRNA mimic. Finally, ex-vivo 9-THC treatment of colon tissue from chronically SIV-infected RMs significantly increased PPAR gene expression. Our findings suggest that dysregulated miR-130a and miR-212 expression in CE during chronic HIV/SIV infection can facilitate epithelial barrier disruption by downregulating OCLN and PPAR protein expression. Most importantly, our results highlight the beneficial effects of cannabinoids on epithelial barrier function in not just HIV/SIV but potentially other chronic intestinal inflammatory diseases.
2018-02-01 | GSE104767 | GEO