Integrative transcriptomic and proteomic analyses reveal that NLRX1 and FASTDK5 orchestrate immunometabolic fitness to fuel HIV-1 replication
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE165841 | GEO | 2021/01/31
REPOSITORIES: GEO
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Project description:Human Immunodeficiency Virus type-1 (HIV-1)-infected individuals show metabolic alterations of CD4 T cells through unclear mechanisms with undefined consequences. We analyzed the transcriptome of CD4 T cells from HIV-1 patients and revealed that elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the FDA-approved drug metformin, which targets mitochondrial respiratory chain complex I, suppresses HIV-1 replication in human CD4 T cells and humanized mice. In patients, HIV-1 peak viremia positively correlates with the expression of NLRX1, a mitochondrial innate immune receptor. Quantitative proteomics and metabolic analyses reveal that NLRX1 enhances OXPHOS and glycolysis during HIV-1-infection of CD4 T cells to promote viral replication. At the mechanistic level, HIV infection induces the association of NLRX1 with the mitochondrial protein, FASTKD5, to promote the expression of mitochondrial respiratory complex components. This study uncovers the OXPHOS pathway in CD4 T cells as a target for HIV-1 therapy.
2022-02-16 | PXD023565 | Pride
Project description:NLRX1 is a mitochondrial-associated NOD-like receptor that modulates antiviral immunity, cellular stress, autophagy, and reactive oxygen species (ROS) production. The role of NLRX1 in inflammatory bowel disease (IBD) remains largely unknown. This study aimed to characterize NLRX1-mediated mechanisms of protection from IBD. We investigated the ability of NLRX1 to modulate global colonic gene expression, gut pathology, inflammation and immunity by using loss-of-function approaches in dextran sodiu sulfate (DSS) and CD4+CD45RBhigh transfer colitis models. Colons, spleens, and mesenteric lymph nodes (MLN) were excised for characterizing immune cell subsets, histological analyses, cytokine, RNA sequencing analyses, and autophagy expression, NF-κB activity, and ROS production. The loss of NLRX1 increased severity of disease and colonic histopathology in both models of IBD. Colons of NLRX1-/- mice had significantly increased epithelial ulceration and leukocyte infiltration mostly in the form of neutrophils, lymphocytes, and macrophages in the DSS model, while recipients of NLRX1-/- CD4+ T cells had increased leukocytic infiltration, proliferation, fibrosis, and crypt abscessation in both colon and ileum. The loss of NLRX1 increased numbers of effector T helper (Th1), Th17, and regulatory T cells (Treg) cells in the colonic mucosa and spleen, increased colonic NF-κB activity, upregulation of IL-17, IFNγ and TNF-α production, and increased ROS production. Global transcriptomic analyses demonstrates that NLRX1 regulates immunity and lipid metabolism pathways. NLRX1 ameliorates intestinal pathology during IBD by acting as an internal thermostat that modulates the balance of effector versus regulatory CD4+ T cell responses, and suppressing colonic NF-κB activity, inflammatory cytokine expression, lipid metabolism gene expression, ROS production and autophagy.
2018-03-07 | GSE68419 | GEO
Project description:Integrative transcriptomic and proteomic analyses reveal that NLRX1 and FASTDK5 orchestrate immunometabolic fitness to fuel HIV-1 replication
| PRJNA698227 | ENA
Project description:The immune signaling protein NLRX1 can be either tumor promoting or tumor suppressing in different models of cancer. We demonstrate that in a mammary tumor model of triple-negative breast cancer, NLRX1 impacts tumor volume and lung metastasis. We used this microarray to understand what genes and pathways are impacted by NLRX1 in murine triple-negative mammary tumors to produce the in vivo phenotypes we observed. Abstract from associated publication: Prior studies have defined multiple, but inconsistent, roles for NLRX1 in regulating cancer-associated biological functions. Here, we explore the role of NLRX1 in the highly-metastatic murine 4T1 mammary tumor model. Using Nlrx1-/- mice engrafted with 4T1 tumors, we demonstrate that NLRX1 functions as a tumor suppressor when expressed in healthy host cells. Specifically, NLRX1 attenuates tumor growth and metastasis through suppressing epithelial-mesenchymal transition, tumor-associated eosinophil recruitment, and the lung metastatic niche. Conversely, we demonstrate that NLRX1 functions as a tumor promoter when expressed in 4T1 tumor cells using gain- and loss-of-function studies. Mechanistically, NLRX1 augments 4T1 aggressiveness through regulating epithelial-mesenchymal transition, cell death, proliferation, migration, ROS levels, and mitochondrial respiration. Together, we provide critical insight into NLRX1 function in breast cancer and establish cellular context as the director of the dichotomous role of NLRX1 in mammary tumor metastasis.
2023-08-01 | GSE216937 | GEO
Project description:NLRX1 is an immune signaling protein that has shown to be both tumor suppressing or tumor promoting, depending on the type of cancer. We demonstrate that NLRX1 has tumor suppressive abilities in vitro in Pan02 cells. We used this microarray to evaluate genes and pathways NLRX1 regulates in these cells to cause the observed in vitro phenotypes. Abstract from associated publication: Pancreatic cancer is a deadly malignancy with limited treatment options. NLRX1 is a unique, understudied member of the Nod-like Receptor (NLR) family of pattern recognition receptors that regulates a variety of biological processes that are highly relevant to pancreatic cancer. The role of NLRX1 in cancer remains highly enigmatic, with some studies defining its roles as a tumor promoter, while others characterize its contributions to tumor suppression. These seemingly contradicting roles appear to be due, at least in part, to cell type and temporal mechanisms. Here, we define roles for NLRX1 in regulating critical hallmarks of pancreatic cancer using both gain-of-function and loss-of-function studies in murine Pan02 cells. Our data reveals that NLRX1 increases susceptibility to cell death, while also suppressing proliferation, migration, and reactive oxygen species production. We also show that NLRX1 protects against upregulated mitochondrial activity and limits energy production in the Pan02 cells. Transcriptomics analysis revealed that the protective phenotypes associated with NLRX1 are correlated with attenuation of NF-kB, MAPK, AKT, and inflammasome signaling. Together, these data demonstrate that NLRX1 diminishes cancer-associated biological functions in pancreatic cancer cells and establishes a role for this unique NLR in tumor suppression.
2023-05-25 | GSE233493 | GEO
Project description:Elite Long-Term Nonprogressors are asymptomatic HIV-infected individuals who display long-term virtually undetectable viremia, stable CD4 T cell counts and extremeley low levels of HIV reservoir, in the absence of antiretroviral therapy. We conducted a whole-genome transcriptional profiling study of sorted resting CD4 T cell subsets (naive, central memory, transitional memory and effector memory) in 7 Elite Long-Term Nonprogressors, 7 HIV-infected viremic and 7 uninfected individuals. HIV-1 cellular DNA levels were quantified in each sorted CD4 T cell subset
2015-01-10 | E-MTAB-1480 | biostudies-arrayexpress
Project description:The clonal expansion of HIV-1-infected CD4+ T cells is a major barrier to cure. Using single-cell ECCITE-seq, we examined the transcriptional landscape, upstream immune regulators, HIV-1 RNA expression, and T cell clonal expansion dynamics of 215,458 CD4+ T cells (267 HIV-1 RNA+ cells and 68 expanded HIV-1 RNA+ T cell clones) from six HIV-1-infected individuals (during viremia and after suppressive antiretroviral therapy) and two uninfected individuals, in unstimulated conditions and after CMV and HIV-1 antigen stimulation. We found that despite antiretroviral therapy, antigen and TNF responses persisted and shaped T cell clonal expansion. HIV-1 resided in Th1 polarized, antigen-responding T cells expressing Bcl-2 family anti-apoptotic genes. HIV-1 RNA+ T cell clones were larger in clone size, established during viremia, persistent after viral suppression, and enriched in GZMB+ cytotoxic effector memory Th1 cells. Targeting HIV-1-infected cytotoxic CD4+ T cells and drivers of clonal expansion provides a new direction for HIV-1 eradication.
2022-03-21 | GSE187515 | GEO
Project description:High levels of HIV-1 replication during the chronic phase of infection are usually associated with rapid disease progression (RP). However, a minority of HIV-infected individuals remain asymptomatic and show persistently high CD4+ T cell counts despite high viremia for many years (viremic non progressors, VNP). The latter profile is reminiscent of the non-pathogenic model of SIV infection in natural hosts such as the sooty mangabey. We used various genomic approaches to examine 66 RP and 6 VNP defined according to strict criteria. RP were characterized by depletion of protective HLA alleles, enrichment of HLA alleles associated with disease progression, and a characteristic transcriptome profile of CD4+ and CD8+ T cells similar to that observed in pathogenic SIV infection of rhesus macaque. In contrast, VNPs presented lower expression of interferon stimulated genes than RP, and shared with SIV-infected sooty mangabeys a common profile of regulation of a set of genes that includes CASP1, CD38, LAG3, TNFSF13B, SOCS1 and EEF1D. The estimated 8% of RP and 0.1% of VNP in human cohorts represent two subsets of HIV-infected individuals whose analysis may inform our understanding of HIV pathogenesis. Selection criteria rapid progressors (RP): HIV seroconversion window <1 year WITH documented negative and positive serology or biological proof of primary infection. AND One of A) or B) A) >2 CD4+ T cell counts below 350 cells/µl within 3 years of seroconversion AND no subsequent rise of CD4+ T cells above 350 cells/µl in the absence of ART. B) ART initiated within 3 years of seroconversion AND CD4+ T cell count within 1 month of ART-start <350 cells/µl. Selection criteria viremic non progressors (VNP): > 3 years of follow-up AND median HIV viremia from >3 measurements >100'000 viral RNA copies/ml AND HIV viremia consistently above 10’000 copies/ml AND CD4+ T cell count above 350 cells/µl AND no ART during follow-up. Selection criteria elite/viremic controllers (EC): see Casado et al. 2010. Host and viral genetic correlates of clinical definitions of HIV-1 disease progression. PLoS ONE 5:e11079. Total RNA from 41 samples obtained from CD4 T cells from HIV infected individuals to identify associations between gene expression and different distinct patterns of disease progression Total RNA from 38 samples obtained from CD8 T cells from HIV infected individuals to identify associations between gene expression and different distinct
2011-06-03 | E-GEOD-28128 | biostudies-arrayexpress
Project description:Longitudinal analysis of monocyte gene expressions patterns before and after cessation of HAART: understanding the impact of HIV viremia on the monocyte tranascritome. We used microarrays to detail the global program of gene expression underlying defects in monocytes from HIV infected patients during viremia.. Diminished Production of Monocyte Proinflammatory Cytokines During HIV Viremia is Mediated by Interferon-alpha: The in vivo effect of high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated spontaneous production of monocyte proinflammatory cytokines (IL-1?, IL-6, and TNF-?) compared to uninfected controls. These levels were highest in patients on-therapy and was diminished, in the context of viremia, following an interruption of therapy. Diminished production of proinflammatory cytokines during viremia was restored by culturing with autologous CD4+ T cells or monocytes from an on-therapy time point, or by the addition of lipopolysaccharide (LPS). Microarray analysis demonstrated that diminished monocyte production of proinflammatory cytokines was correlated with elevated levels of type I interferon-stimulated gene transcripts. Addition of exogenous IFN-?2A suppressed the spontaneous production of IL-1?, IL-6, and TNF-? but did not affect responses to LPS, recapitulating the changes observed in HIV viremic patients. These results suggest that high-level HIV viremia inhibits monocyte function through chronic stimulation by IFN-?. This effect of viremia on monocytes may play a role in diminished adaptive immune system functions in HIV-infected patients. Restoration of these functions may contribute to the partial immune reconstitution observed following therapy and may be involved in immune reconstitution and inflammatory syndrome seen in some patients. Keywords: Longitudinal comparison
2006-07-04 | GSE5220 | GEO
Project description:The effect of human immunodeficiency virus (HIV) infection and high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated levels of spontaneous production of some or all of the monocyte proinflammatory cytokines measured (interleukin-1beta [IL-1beta], IL-6, and tumor necrosis factor alpha [TNF-alpha]) compared to uninfected controls. In patients on therapy with high frequencies of monocytes producing proinflammatory cytokines, this frequency was diminished in the context of viremia during an interruption of therapy. Diminished production of proinflammatory cytokines during viremia was restored by culture with autologous CD4(+) T cells or monocytes from an on-therapy time point or lipopolysaccharide (LPS). Microarray analysis demonstrated that diminished monocyte production of proinflammatory cytokines was correlated with elevated type I interferon-stimulated gene transcripts. The addition of exogenous alpha 2A interferon diminished the spontaneous production of IL-1beta, IL-6, and TNF-alpha but did not affect responses to LPS, recapitulating the changes observed for HIV-viremic patients. These results suggest that monocyte function is diminished during high-level HIV viremia and that this effect is mediated by chronic stimulation by type I interferons. This effect on monocytes during viremia may play a role in diminished innate or adaptive immune system functions in HIV-infected patients. In addition, the restoration of these functions may also play a role in some immune reconstitution syndromes observed during initiation of therapy.
2007-10-26 | E-GEOD-5220 | biostudies-arrayexpress