scholarly journals Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis

2020 ◽  
Author(s):  
Clare Eckold ◽  
Vinod Kumar ◽  
January Weiner ◽  
Bachti Alisjahbana ◽  
Anca-Lelia Riza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Expression Change ◽  
Tb Treatment ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Transcriptomic Signature ◽  
Interferon Responses

Abstract Background People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Results Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.

scholarly journals NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses

2021 ◽  
Author(s):  
Hongyun Wang ◽  
Lu Zhang ◽  
Cong Zeng ◽  
Jiangpeng Feng ◽  
Yu Zhou ◽  
...  
Keyword(s):  
Viral Infection ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Negative Regulator ◽  
Interferon Response ◽  
Rna Modification ◽  
Type I ◽  
Mrna Levels ◽  
Interferon Responses

5-Methylcytosine (m5C) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes through regulating RNA metabolism. However, its regulatory role in antiviral innate immunity has not yet been elucidated. Here, we report that NSUN2, a typical m5C methyltransferase, can negatively regulate type I interferon responses during viral infection. NSUN2 specifically mediates m5C methylation of IRF3 mRNA and accelerates its degradation, resulting in low levels of IRF3 and downstream IFN-β production. Knockout or knockdown of NSUN2 could enhance type I interferon responses and downstream ISG expression after viral infection in vitro. And in vivo, the antiviral innate responses is more dramatically enhanced in Nsun2+/− mice than in Nsun2+/+ mice. Four highly m5C methylated cytosines in IRF3 mRNA were identified, and their mutation could enhance the cellular IRF3 mRNA levels. Moreover, infection with Sendai virus (SeV), vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), Zika virus (ZIKV), or especially SARS-CoV-2 resulted in a reduction in endogenous levels of NSUN2. Together, our findings reveal that NSUN2 serves as a negative regulator of interferon response by accelerating the fast turnover of IRF3 mRNA, while endogenous NSUN2 levels decrease after viral infection to boost antiviral responses for the effective elimination of viruses. Our results suggest a paradigm of innate antiviral immune responses ingeniously involving NSUN2-mediated m5C modification.

scholarly journals Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation

2021 ◽  
Vol 22 (3) ◽  
pp. 1301
Author(s):  
Ioannis Kienes ◽  
Tanja Weidl ◽  
Nora Mirza ◽  
Mathias Chamaillard ◽  
Thomas A. Kufer
Keyword(s):  
Viral Infections ◽  
Type I Interferon ◽  
Tissue Injury ◽  
Interferon Response ◽  
Type I ◽  
Interferon Signaling ◽  
Microbial Products ◽  
Interferon Responses

Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.

scholarly journals Suppression of Type I Interferon Signaling by E1A via RuvBL1/Pontin

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Oladunni Olanubi ◽  
Jasmine Rae Frost ◽  
Sandi Radko ◽  
Peter Pelka
Keyword(s):  
Gene Expression ◽  
Cellular Response ◽  
Type I Interferon ◽  
Early Gene ◽  
Interferon Response ◽  
Type I ◽  
Dependent Manner ◽  
Interferon Signaling ◽  
Interferon Pathway ◽  
Regulated Promoters

ABSTRACT Suppression of interferon signaling is of paramount importance to a virus. Interferon signaling significantly reduces or halts the ability of a virus to replicate; therefore, viruses have evolved sophisticated mechanisms that suppress activation of the interferon pathway or responsiveness of the infected cell to interferon. Adenovirus has multiple modes of inhibiting the cellular response to interferon. Here, we report that E1A, previously shown to regulate interferon signaling in multiple ways, inhibits interferon-stimulated gene expression by modulating RuvBL1 function. RuvBL1 was previously shown to affect type I interferon signaling. E1A binds to RuvBL1 and is recruited to RuvBL1-regulated promoters in an interferon-dependent manner, preventing their activation. Depletion of RuvBL1 impairs adenovirus growth but does not appear to significantly affect viral protein expression. Although RuvBL1 has been shown to play a role in cell growth, its depletion had no effect on the ability of the virus to replicate its genome or to drive cells into S phase. E1A was found to bind to RuvBL1 via the C terminus of E1A, and this interaction was important for suppression of interferon-stimulated gene transcriptional activation and recruitment of E1A to interferon-regulated promoters. Here, we report the identification of RuvBL1 as a new target for adenovirus in its quest to suppress the interferon response. IMPORTANCE For most viruses, suppression of the interferon signaling pathway is crucial to ensure a successful replicative cycle. Human adenovirus has evolved several different mechanisms that prevent activation of interferon or the ability of the cell to respond to interferon. The viral immediate-early gene E1A was previously shown to affect interferon signaling in several different ways. Here, we report a novel mechanism reliant on RuvBL1 that E1A uses to prevent activation of interferon-stimulated gene expression following infection or interferon treatment. This adds to the growing knowledge of how viruses are able to inhibit interferon and identifies a novel target used by adenovirus for modulation of the cellular interferon pathway.

scholarly journals ALG2 regulates type I interferon responses by inhibiting STING trafficking

2021 ◽  
Author(s):  
Wangsheng Ji ◽  
Lianfei Zhang ◽  
Xiaoyu Xu ◽  
Xinqi Liu
Keyword(s):  
Immune Responses ◽  
Type I Interferon ◽  
Innate Immune ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Innate Immune Responses ◽  
Downstream Signaling ◽  
Interferon Responses ◽  
Hsv 1

Stimulator of IFN genes (STING), an endoplasmic reticulum (ER) signaling adaptor, is essential for the type I interferon response to cytosolic dsDNA. The translocation from the ER to perinuclear vesicles following binding cGAMP is a critical step for STING to activate downstream signaling molecules, which lead to the production of interferon and pro-inflammatory cytokines. Here we found that apoptosis-linked gene 2 (ALG2) suppressed STING signaling induced by either HSV-1 infection or cGAMP presence. Knockout of ALG2 markedly facilitated the expression of type I interferons upon cGAMP treatment or HSV-1 infection in THP-1 monocytes. Mechanistically, ALG2 associated with the C-terminal tail (CTT) of STING and inhibited its trafficking from ER to perinuclear region. Furthermore, the ability of ALG2 to coordinate calcium was crucial for its regulation of STING trafficking and DNA-induced innate immune responses. This work suggests that ALG2 is involved in DNA-induced innate immune responses by regulating STING trafficking.

scholarly journals Interferon- and STING-independent induction of type I interferon stimulated genes during fractionated irradiation

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Ruben S. A. Goedegebuure ◽  
Esther A. Kleibeuker ◽  
Francesca M. Buffa ◽  
Kitty C. M. Castricum ◽  
Syed Haider ◽  
...  
Keyword(s):  
Gene Expression ◽  
Esophageal Cancer ◽  
Cancer Patients ◽  
Cell Lines ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Fractionated Irradiation

Abstract Background Improvement of radiotherapy efficacy requires better insight in the dynamic responses that occur during irradiation. Here, we aimed to identify the molecular responses that are triggered during clinically applied fractionated irradiation. Methods Gene expression analysis was performed by RNAseq or microarray analysis of cancer cells or xenograft tumors, respectively, subjected to 3–5 weeks of 5 × 2 Gy/week. Validation of altered gene expression was performed by qPCR and/or ELISA in multiple cancer cell lines as well as in pre- and on-treatment biopsies from esophageal cancer patients (NCT02072720). Targeted protein inhibition and CRISPR/Cas-induced gene knockout was used to analyze the role of type I interferons and cGAS/STING signaling pathway in the molecular and cellular response to fractionated irradiation. Results Gene expression analysis identified type I interferon signaling as the most significantly enriched biological process induced during fractionated irradiation. The commonality of this response was confirmed in all irradiated cell lines, the xenograft tumors and in biopsies from esophageal cancer patients. Time-course analyses demonstrated a peak in interferon-stimulated gene (ISG) expression within 2–3 weeks of treatment. The response was accompanied by a variable induction of predominantly interferon-beta and/or -lambda, but blocking these interferons did not affect ISG expression induction. The same was true for targeted inhibition of the upstream regulatory STING protein while knockout of STING expression only delayed the ISG expression induction. Conclusions Collectively, the presented data show that clinically applied fractionated low-dose irradiation can induce a delayed type I interferon response that occurs independently of interferon expression or STING signaling. These findings have implications for current efforts that aim to target the type I interferon response for cancer treatment.

scholarly journals P145 Computational analysis of neutrophil gene expression reveals activation signatures associated with DMARD refractory rheumatoid arthritis

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_1) ◽  
Author(s):  
Michele Fresneda Alarcon ◽  
Eva Caamano-Gutierrez ◽  
Philipp Antczak ◽  
Robert J Moots ◽  
Helen L Wright
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Amino Acid ◽  
Gene Networks ◽  
Type I Interferon ◽  
Computational Modelling ◽  
Gene Expression Signature ◽  
Interferon Response ◽  
Type I ◽  
Healthy Controls

Abstract Background/Aims  Neutrophils contribute to disease pathology in inflammatory diseases including rheumatoid arthritis (RA). Activated RA neutrophils release ROS and proteases which damage joints, and produce neutrophil extracellular traps (NETs) that expose citrullinated nuclear proteins leading to the development of ACPA auto-antibodies. We previously described an altered gene expression signature in RA patients compared to healthy controls. This aim of this work was to use computational modelling of neutrophil transcriptomes to provide novel insight into the physiological factors controlling neutrophil phenotype in RA. Methods  RNA from peripheral blood neutrophils (RA patients (DAS28>5.1, cohort 1 n = 23, cohort 2 n = 53), healthy controls (n = 11)) was sequenced using RNAseq. Reads were mapped to the human genome (hg38) using Tophat2 and read counts generated using featureCounts. Partial least squares discriminant analysis (PLS-DA) was carried out using mixOmics (with random sampling and ‘leave one out’ cross-validation). Gene expression network analysis was carried out using tmod, ARACNE2 and GALGO. Gene networks were visualised using Cytoscape. Functional annotation was carried out using Ingenuity Pathway Analysis (IPA) and DAVID. Results  PLS-DA modelling discriminated RA and HC neutrophil transcriptomes with an F1 score of 98.2% +/- 1.6% over 5 repetitions using a model with 1 component. Blood transcriptional modular (tmod) enrichment analysis of gene expression in RA and HC neutrophils from cohort 1 identified the gene networks activated in RA and absent in HC as: myeloid cells activated via NFκB, innate antiviral response, type I interferon response, inflammasome receptors and cell signalling (FDR<0.05, AUC >0.8). Cell cycle and growth arrest was also considerably more enriched in RA compared to HC (RA AUC=0.82, HC AUC=0.57). Activation of type I interferon and inflammasome signalling pathways in cohort 1 was confirmed by IPA and correlated closely with data from a second cohort of RA patients (cohort 2). ARACNE2 identified five major gene modules activated in RA neutrophils (MI threshold 0.5, p < 10-20). IPA and DAVID predicted that Module 1 gene networks regulated amino acid, nucleic acid, carbohydrate and lipid metabolism as well as initiation of gene expression. Module M2 contained a network of genes regulated by integrins and cytokine receptors (e.g. IL-8, JAK/STAT, TNF/NFκB). Module 3 also contained genes activated by NFκB as well as by AMP-protein kinase. Module M4 genes were regulated by activation of type I interferon receptors and pattern recognition receptors (e.g. IRFs, STATs). Module M5 genes regulated amino acid metabolism. Multivariate modelling using GALGO identified genes that predict clinical characteristics, including genes involved in NFκB signalling, apoptosis and kinase activation which were associated with disease activity (DAS28), and cellular stress response genes and chromatin modification that was associated with raised inflammatory markers (ESR, CRP). Conclusion  The results of the computational analyses are currently being validated experimentally. Disclosure  M. Fresneda Alarcon: None. E. Caamano-Gutierrez: None. P. Antczak: None. R.J. Moots: None. H.L. Wright: Grants/research support; H.W. has received funding from Versus Arthritis and the Masonic Charitable Fund.

scholarly journals Dual Feedforward Loops Modulate Type I Interferon Responses and Induce Selective Gene Expression during TLR4 Activation

iScience ◽  
2020 ◽  
Vol 23 (2) ◽  
pp. 100881
Author(s):  
Jie Zhou ◽  
Tingzhe Sun ◽  
Shouheng Jin ◽  
Zhiyong Guo ◽  
Jun Cui
Keyword(s):  
Gene Expression ◽  
Type I Interferon ◽  
Type I ◽  
Tlr4 Activation ◽  
Interferon Responses

scholarly journals Loss of mitochondrial protease CLPP activates type I interferon responses through the mtDNA-cGAS-STING signaling axis

2020 ◽  
Author(s):  
Sylvia Torres-Odio ◽  
Yuanjiu Lei ◽  
Suzana Gispert ◽  
Antonia Maletzko ◽  
Jana Key ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Type I Interferon ◽  
Type I ◽  
Signaling Axis ◽  
Perrault Syndrome ◽  
Immune Pathway ◽  
Interferon Responses ◽  
Antiviral Gene ◽  
Innate Immune Pathway

AbstractCaseinolytic mitochondrial matrix peptidase proteolytic subunit, CLPP, is a serine protease that degrades damaged or misfolded mitochondrial proteins. CLPP null mice exhibit growth retardation, deafness, and sterility, resembling human Perrault syndrome (PS), but also display immune system alterations. However, the molecular mechanisms and signaling pathways underlying immunological changes in CLPP null mice remain unclear. Here we report the steady state activation of type I interferon (IFN-I) signaling and antiviral gene expression in CLPP deficient cells and tissues. Depletion of the cyclic GMP-AMP (cGAS)-Stimulator of Interferon Genes (STING) DNA sensing pathway ablates heightened IFN-I responses and abrogates the broad viral resistance phenotype of CLPP null cells. Moreover, we report that CLPP deficiency leads to mitochondrial DNA (mtDNA) instability and packaging alterations. Pharmacological and genetic approaches to deplete mtDNA or inhibit cytosolic release markedly reduce antiviral gene expression, implicating mtDNA stress as the driver of IFN-I signaling in CLPP null mice. Our work places the cGAS-STING-IFN-I innate immune pathway downstream of CLPP and may have implications for understanding myriad human diseases involving CLPP dysregulation.

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