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Identification and validation of Ifit1 as an important innate immune bottleneck.

ABSTRACT: The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates the utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes.

SUBMITTER: McDermott JE

PROVIDER: S-EPMC3380000 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Identification and validation of Ifit1 as an important innate immune bottleneck.

McDermott Jason E JE Vartanian Keri B KB Mitchell Hugh H Stevens Susan L SL Sanfilippo Antonio A Stenzel-Poore Mary P MP

PloS one 20120620 6

The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune ...[more]

PMID: 22745654

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Project description:BackgroundEarly biomarkers of progression to severe dengue are urgently required to enable effective patient management and control treatment costs. Innate immune cells, which comprise the earliest responders to infection and along with the cytokines and chemokines they secrete, play a vital role in orchestrating the subsequent adaptive immune response and have been implicated in the enhancement of infection and "cytokine storm" associated with dengue severity. We investigated the early innate immune cytokine profile of dengue patients during acute phase of disease in a prospective blinded study that included subjects with acute dengue and febrile controls from four major hospitals in Bengaluru, India along with healthy controls. We used intracellular cytokine staining and flow cytometry to identify innate immune biomarkers that can predict progression to severe dengue.ResultsDengue infection resulted in enhanced secretion of multiple cytokines by all queried innate immune cell subsets, dominated by TNF-α from CD56+CD3+ NKT cells, monocyte subsets, and granulocytes along with IFN-γ from CD56+CD3+ NKT cells. Of note, significantly higher proportions of TNF-α secreting granulocytes and monocyte subsets at admission were associated with mild dengue and minimal symptoms. Dengue NS1 antigenemia used as a surrogate of viral load directly correlated with proportion of cytokine-secreting innate immune cells and was significantly higher in those who went on to recover with minimal symptoms. In patients with secondary dengue or those with bleeding or elevated liver enzymes who revealed predisposition to severe outcomes, early activation as well as efficient downregulation of innate responses were compromised.ConclusionOur findings suggested that faulty/delayed kinetics of innate immune activation and downregulation was a driver of disease severity. We identified IFN-γ +CD56+CD3+ NKT cells and IL-6+ granulocytes at admission as novel early biomarkers that can predict the risk of progression to severity (composite AUC = 0.85-0.9). Strong correlations among multiple cytokine-secreting innate cell subsets revealed that coordinated early activation of the entire innate immune system in response to dengue virus infection contributed to resolution of infection and speedy recovery.

Project description:BackgroundCoronary heart disease (CHD) is an ischemic heart disease involving a variety of immune factors. This study was aimed at investigating unique immune and m6A patterns in patients with CHD by gene expression in peripheral blood mononuclear cells (PBMCs) and at identifying novel immune biomarkers.MethodsThe CIBERSORT algorithm and single-sample gene set enrichment analysis (ssGSEA) were applied to assess the population of specific infiltrating immunocytes. Weighted Gene Coexpression Network Analysis (WGCNA) was utilized on immune genes matching CHD. A prediction model based on core immune genes was constructed and verified by a machine learning model. Unsupervised cluster analysis identified various immune patterns in the CHD group according to the abundance of immune cells. Methylation of N6 adenosine- (m6A-) related gene was identified from the literature, and t-distributed stochastic neighbor embedding (t-SNE) analysis was used to determine the rationality of the m6A classification. The association between m6A-related genes and various immune cells was estimated using heat maps.Results22/28 immune-associated cells differed between the CHD and normal groups, and a significant difference was detected in the expression of 21 m6A-related genes. The proportion of immune-related cells (activated CD4+ T cells and CD8+ T cells) in the peripheral blood of the CHD group was lower than that of the normal group. The immune genes were divided into four modules, of which the turquoise modules showed a significant association with coronary heart disease. Eight hub immune genes (PDGFRA, GNLY, OSMR, NUDT6, FGFR2, IL2RB, TPM2, and S100A1) can well distinguish the CHD group from the normal group. Two different immune patterns were identified in the CHD group. Interestingly, a significant association was detected between the m6A-related genes and immune cell abundance.ConclusionIn conclusion, we identified different immune and m6A patterns in CHD. Thus, it could be speculated that the immune system plays a crucial role in CHD, and m6A is correlated with immune genes.

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Identification and validation of Ifit1 as an important innate immune bottleneck.

Publications

Identification and validation of Ifit1 as an important innate immune bottleneck.

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