ORAI1 establishes resistance to SARS-CoV-2 infection by regulating tonic type I interferon levels
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA726809 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14385317.fastq.gz | Fastqsanger.gz | |||
| SRR14385318.fastq.gz | Fastqsanger.gz | |||
| SRR14385319.fastq.gz | Fastqsanger.gz | |||
| SRR14385320.fastq.gz | Fastqsanger.gz | |||
| SRR14385321.fastq.gz | Fastqsanger.gz |
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Project description:We report RNAseq analysis of control, ORAI1KO and STIM1 KO (knockout) HEK293-ACE2 cells under uninfected (mock) and SARS-CoV-2-infected conditions
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Project description:ORAI1 and STIM1 are the critical mediators of store-operated Ca 2+ entry by acting as the pore subunit and an endoplasmic reticulum-resident signaling molecule, respectively. In addition to Ca 2+ signaling, STIM1 is also involved in regulation of a cytosolic nucleic acid sensing pathway. Using ORAI1 and STIM1 knockout cells, we examined their contribution to the host response to SARS-CoV-2 infection. STIM1 knockout cells showed strong resistance to SARS-CoV-2 infection due to enhanced type I interferon response. On the contrary, ORAI1 knockout cells showed high susceptibility to SARS-CoV-2 infection as judged by increased expression of viral proteins and a high viral load. Mechanistically, ORAI1 knockout cells showed reduced homeostatic cytoplasmic Ca 2+ concentration and severe impairment in tonic interferon signaling. Transcriptome analysis showed downregulation of multiple cellular defense mechanisms, including antiviral signaling pathways in ORAI1 knockout cells, which are likely due to reduced expression of the Ca 2+ -dependent transcription factors of the activator protein 1 (AP-1) family and MEF2C . Our results identify a novel role of ORAI1-mediated Ca 2+ signaling in regulating the baseline type I interferon level, which is a determinant of host resistance to SARS-CoV-2 infection.
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Project description:Positive selection occurs in the thymic cortex, but critical maturation events occur later in the medulla. We defined the precise stage at which T cells acquire competence to proliferate and emigrate. Transcriptome analysis of late gene changes suggested roles for NF-κB and interferon signaling. Mice lacking the IKK kinase TAK1, showed normal positive selection, but a specific block in functional maturation. NF-κB signaling provided protection from TNF, and was required for proliferation and emigration. Alternatively, the interferon signature was independent of NF-κB, and IFNαR deficient thymocytes showed reduced STAT1 levels and phenotypic abnormality, but were competent to proliferate. Thus, both NF-κB and tonic IFN signals are involved in the final maturation of thymocytes into naïve T cells. Gene expression profile was performed on cells isolated from mouse thymus, including Pre-DP, Post-DP, SM&M1, M2 and Tak1-deficient SM&M1 cells.
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Project description:Platelet-derived growth factor (PDGF) signalling and the subsequent activation of the calcium ion channel, ORAI1 are critical drivers of pathological remodelling of native vascular smooth muscle cells to proliferative state, which is a process associated with various vascular diseases. This study aims to reveal transcriptional networks altered following ORAI1 inhibition in vascular smooth muscle cells. To study the effect of ORAI1 inhibition on VSMC biology, we performed RNA-Seq analysis of PDGF-stimulated primary human aortic smooth muscle cells treated with either ORAI1 inhibitor, (n=4) or with vehicle (n=4), and investigated the effect of ORAI1 inhibition on the transcriptional response of cells.
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Project description:Oral cancer causes pain associated with cancer progression. The mechanism(s) underlying the pain is not fully understood. We report here that the function of the Ca2+ channel ORAI1 is an important regulator of oral cancer pain. ORAI1 was highly expressed in tumor samples from oral cancer patients and ORAI1 activation caused sustained Ca2+ influx in human oral cancer cells. RNA-seq analysis showed broad modulation of oral cancer markers such MMPs and pain modulators by ORAI1. Inoculation of oral cancer cells lacking ORAI1 into mouse paws reduced ectopic tumor growth and allodynia, reducing secreted MMP1 levels and the excitation of trigeminal ganglia (TG) neurons. The stimulation of TG neurons with MMP1 evoked an increase in action potentials. These data demonstrate an important role of ORAI1 in oral cancer progression likely by controlling the expression of MMP1 resulting in increased cancer progression and pain
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Project description:Plasmacytoid dendritic cells (pDCs) mount powerful type I interferon (IFN-I) responses against viruses and virus-derived nucleic acids. Only a small fraction of pDCs produces high levels of IFN-I, yet neither the molecular basis nor the purpose of this functional heterogeneity are known. We report that naive murine pDCs comprise three transcriptionally (but not epigenetically) distinct subsets. This heterogeneity is generated by tonic IFN-I signaling elicited in part by the cGAS/STING and TLR9 pathways. A small "IFN-I-naive" subset (pDC-A) was expanded in STING deficiency or after transient IFN-I receptor blockade, but was abolished by exogenous IFN-I. pDC-A showed strong cytokine responses yet were susceptible to infection with vesicular stomatitis virus (VSV). Conversely, the majority of pDCs comprised the "IFN-I-primed" subsets (pDC-B/C) that showed lower IFN-I responses but were resistant to VSV. Thus, tonic IFN-I signaling decreases the cytokine-producing capacity of pDCs but increases their virus resistance, achieving the optimal functional balance for antiviral responses.
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Project description:Tonic type I interferon signaling optimizes the antiviral function of plasmacytoid dendritic cells
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Project description:Plasmacytoid dendritic cells (pDCs) mount powerful type I interferon (IFN-I) responses against viruses and virus-derived nucleic acids. Only a small fraction of pDCs produces high levels of IFN-I, yet neither the molecular basis nor the purpose of this functional heterogeneity are known. We report that naive murine pDCs comprise three transcriptionally (but not epigenetically) distinct subsets. This heterogeneity is generated by tonic IFN-I signaling elicited in part by the cGAS/STING and TLR9 pathways. A small "IFN-I-naive" subset (pDC-A) was expanded in STING deficiency or after transient IFN-I receptor blockade, but was abolished by exogenous IFN-I. pDC-A showed strong cytokine responses yet were susceptible to infection with vesicular stomatitis virus (VSV). Conversely, the majority of pDCs comprised the "IFN-I-primed" subsets (pDC-B/C) that showed lower IFN-I responses but were resistant to VSV. Thus, tonic IFN-I signaling decreases the cytokine-producing capacity of pDCs but increases their virus resistance, achieving the optimal functional balance for antiviral responses.
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Project description:ORAI1 and stromal interaction molecule 1 (STIM1) are the critical mediators of store-operated Ca2+ entry by acting as the pore subunit and an endoplasmic reticulum-resident signaling molecule, respectively. In addition to Ca2+ signaling, STIM1 is also involved in regulation of the type I IFN (IFN-I) response. To examine their potential role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we generated ORAI1 and STIM1 knockout human HEK293-angiotensin-converting enzyme 2 cells and checked their responses. STIM1 knockout cells showed strong resistance to SARS-CoV-2 infection as a result of enhanced IFN-I response. On the contrary, ORAI1 deletion induced high susceptibility to SARS-CoV-2 infection. Mechanistically, ORAI1 knockout cells showed reduced homeostatic cytoplasmic Ca2+ concentration and severe impairment in tonic IFN-I signaling. Transcriptome analysis showed downregulation of multiple antiviral signaling pathways in ORAI1 knockout cells, likely because of reduced expression of the Ca2+-dependent transcription factors of the AP-1 family and MEF2C Accordingly, modulation of homeostatic Ca2+ concentration by pretreatment with ORAI1 blocker or agonist could influence baseline IFNB expression and resistance to SARS-CoV-2 infection in a human lung epithelial cell line. Our results identify a novel role of ORAI1-mediated Ca2+ signaling in regulating the tonic IFN-I levels, which determine host resistance to SARS-CoV-2 infection.
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