Restoring a homeostatic microglia state by combination antiretroviral therapy in SIV-infected rhesus macaques
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ABSTRACT:
PROVIDER: PRJNA801267 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17790800.fastq.gz | Fastqsanger.gz | |||
| SRR17790801.fastq.gz | Fastqsanger.gz | |||
| SRR17790802.fastq.gz | Fastqsanger.gz | |||
| SRR17790803.fastq.gz | Fastqsanger.gz | |||
| SRR17790804.fastq.gz | Fastqsanger.gz |
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2022-06-22 | GSE195574 | GEO
Project description:Microglia and macrophages are essential for homeostatic maintenance and innate immune response in the brain. They are the first line of defense against infections such as HIV/SIV in the brain. However, they are susceptible to infection and function as viral reservoirs even under effective viral suppression. While current antiretroviral regimens successfully suppress viremia and improve quality of life and lifespan, neurologic complications persist and are in part attributed to activated microglia. We sought to test the hypothesis that brain microglia return to a more homeostatic-like state when viremia is suppressed by combination antiretroviral therapy. Using the SIV-rhesus macaque model, we combined single-cell RNA sequencing, bioinformatics, and pathway analysis to compare gene expression profiles of brain myeloid cells under 4 conditions: uninfected, SIV infected, SIV infected with cART suppression, and SIV encephalitis (SIVE). Our study reveals greater myeloid diversity and an elevated proinflammatory state are associated with untreated SIV infection compared with uninfected animals. The development of encephalitis and suppression of viremia both reduced myeloid diversity. However, they had converse effects on the activation state of microglia and inflammation. Notably, suggestive of a restoration of a homeostatic state in microglia, gene expression and activation of pathways related to inflammation and immune response in cART-suppressed monkeys were most similar to that in uninfected monkeys. Untreated SIV infection shared characteristics, especially in brain macrophages to SIVE, with SIVE showing dramatic inflammation. In support of our hypothesis, our study demonstrates that cART indeed restores this key component of the brain's homeostatic state. Summary: ScRNA-seq of rhesus monkey microglia reveals clusters of cells in activated states in the setting of SIV infection, which is primarily reversed by suppressing viremia with combination antiretroviral therapy.
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Project description:HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation, which are not completely ameliorated with suppression of viremia by antiretroviral (ARV) therapy. Furthermore, increased morbidity and mortality of ARV-treated HIV-infected individuals is associated with these dysfunctions. Thus, in order to enhance GI tract immunity, we treated SIV-infected pigtail macaques with ARVs supplemented with probiotics and prebiotics or with ARVs alone. In the colon, this synbiotic treatment resulted in increased expression of genes associated with antigen presenting cells (APCs), increased frequency and functionality of APCs, enhanced reconstitution and functionality of CD4+ T-cells and reduced fibrosis of lymphoid follicles. Thus, supplementing ARV treatment with synbiotic treatment in HIV-infected individuals may improve GI tract immunity and thereby mitigate inflammatory sequelae, ultimately improving prognosis. CD45+ (clone MB4-6D6) leukocytes were sorted from thawed colon samples from 4 ARV + probiotics animals and 4 ARV alone animals
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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.
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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.
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Project description:HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation, which are not completely ameliorated with suppression of viremia by antiretroviral (ARV) therapy. Furthermore, increased morbidity and mortality of ARV-treated HIV-infected individuals is associated with these dysfunctions. Thus, in order to enhance GI tract immunity, we treated SIV-infected pigtail macaques with ARVs supplemented with probiotics and prebiotics or with ARVs alone. In the colon, this synbiotic treatment resulted in increased expression of genes associated with antigen presenting cells (APCs), increased frequency and functionality of APCs, enhanced reconstitution and functionality of CD4+ T-cells and reduced fibrosis of lymphoid follicles. Thus, supplementing ARV treatment with synbiotic treatment in HIV-infected individuals may improve GI tract immunity and thereby mitigate inflammatory sequelae, ultimately improving prognosis.
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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.
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Project description:The study describes miRNA expression changes in basal ganglia (BG) of chronically SIV-infected rhesus macaques. HIV/SIV-associated neurological disorder (HAND) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Employing a systems biology approach, we report molecular changes underlying HAND and its modulation by phytocannabinoids [delta-9-tetrahydrocannabinol (9-THC)] in uninfected and SIV-infected rhesus macaques (RMs) treated with vehicle (VEH/SIV) or 9-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-endoplasmic reticulum (WFS1) and anti-oxidative stress (CRYM) proteins that were significantly downregulated in BG of VEH/SIV RMs. Both proteins localized to the BG neurons, and showed differential expression in the BG of THC/SIV and VEH/SIV RMs. Additionally, inflammation-associated miR-155 and miR-142-3p showed significantly higher expression in the BG of VEH/SIV RMs. In human primary HCN2 neuronal cells, miR-142-3p post-transcriptionally downregulated WFS1. These findings strongly support a role for differential miRNA expression associated with HIV/SIV induced neurological dysfunction.
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