A critical role for STING signaling in limiting pathogenesis of Chikungunya virus
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ABSTRACT:
PROVIDER: PRJNA668984 | ENA |
REPOSITORIES: ENA
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Project description:The stimulator-of-interferon-gene (STING) pathway controls both DNA and RNA virus infection. STING is essential for induction of innate immune responses during DNA virus infection, while its mechanism against RNA virus remains largely elusive. We show that STING signaling is crucial for restricting Chikungunya virus infection and arthritis pathogenesis. Sting-deficient mice (Stinggt/gt) had elevated viremia throughout the viremic stage and viral burden in the feet transiently, along with a normal type I IFN response. Stinggt/gt mice presented much greater foot swelling, joint damage and immune cell infiltration than WT mice. Intriguingly, expression of interferon gamma and its induced Cxcl10 was continuously upregulated by ~7-10-fold, and further elevated in Stinggt/gt mice synchronously with arthritis progression. However, expression of chemoattractants for and activators of neutrophils, Cxcl5, Cxcl7 and Cxcr2 was suppressed in Stinggt/gt joints. These results demonstrate that STING deficiency leads to an aberrant chemokine response that promotes pathogenesis of CHIKV arthritis.
2020-10-14 | GSE159450 | GEO
Project description:The stimulator of interferon gene (STING) pathway controls both DNA and RNA virus infection. STING is essential for induction of innate immune responses during DNA virus infection, while its mechanism against RNA virus remains largely elusive. We show that STING signaling is crucial for restricting chikungunya virus infection and arthritis pathogenesis. Sting-deficient mice (Stinggt/gt) had elevated viremia throughout the viremic stage and viral burden in feet transiently, with a normal type I IFN response. Stinggt/gt mice presented much greater foot swelling, joint damage, and immune cell infiltration than wild-type mice. Intriguingly, expression of interferon-γ and Cxcl10 was continuously upregulated by approximately 7 to 10-fold and further elevated in Stinggt/gt mice synchronously with arthritis progression. However, expression of chemoattractants for and activators of neutrophils, Cxcl5, Cxcl7, and Cxcr2 was suppressed in Stinggt/gt joints. These results demonstrate that STING deficiency leads to an aberrant chemokine response that promotes pathogenesis of CHIKV arthritis.
| S-EPMC8205639 | biostudies-literature
Project description:In this study, we aim to identify common host genes involved in pathogenesis of different Chikungunya virus strains as an attempt to recognize probable antiviral targets. We have compared the host gene regulation after infection of monkey kidney cell line (Vero) with two different wild type CHIKV strains i.e. S 27 (human, ECSA), and DRDE-06 (human, ECSA). Vero cells were mock infected or infected with two Chikungunya virus strains (S 27 and DRDE-06) and harvested at 8hpi and 18hpi. The total RNA was extracted and microarray was done using Agilent protocol.
2021-10-28 | E-MTAB-6645 | biostudies-arrayexpress
Project description:Chikungunya virus (CHIKV) is a mosquito-borne virus that causes acute, subacute, and chronic human diseases and can cause neurological complications and death. Here, we combined epidemiological, virological, histopathological, cytokine, molecular dynamics, metabolomics, proteomics, and genomic analyses to investigate viral and pathophysiologic factors that contribute to deaths caused by chikungunya (CHIK). Our results indicate that CHIK-deaths presented multiple organs infection, central nervous system damage, and exhibited significantly elevated serum levels of pro-inflammatory cytokines and chemokines compared to survivors. The histopathology, metabolite, and proteomic signatures of CHIK-deaths revealed hemodynamic disorders and dysregulated immune system response. CHIKV East-Central-South-African lineage caused fatal and survivor cases, and CHIKV crosses the blood–brain barrier without tight junction alterations. IFN-λ3 was highly expressed in fatal cases but did not present a direct antiviral effect on CHIKV replication in vitro. In summary, our results reveal insights to improve understanding of CHIK pathogenesis, especially the pathophysiology of fatal infections.
2024-06-16 | PXD043815 | Pride
Project description:Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. Using isotope tracer analysis, we show that type I interferon (IFN) signaling rapidly shifts the balance of these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol, and could be inhibited by replenishing cells with free cholesterol. Taken together, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity. shRNA to SREBF1 (shSREBP1) or SREBF2 (shSREBP2) were stably introduced via 3rd generation lentivirus into human THP1 monocytic cells under puromycin selection. Non-targeting shRNA scramble was used for a control (shControl). shControl, shSREBP1 and shSREBP2 modified cell types were analyzed by RNA-seq in duplicate.
2015-12-10 | E-GEOD-73942 | biostudies-arrayexpress
Project description:Cyclic GMP–AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), form a central cytosolic DNA–sensing pathway that drives innate immune activation and pro-inflammatory cytokine production. We previously reported that cGAS is upregulated in Huntington disease (HD) cellular models, where it modulates autophagy and inflammatory signaling. However, its in vivo contribution to HD pathogenesis has remained unresolved. Here, we genetically ablated cGAS in zQ175 knock-in HD mice, a model that closely recapitulates hallmark features of human HD, and conducted longitudinal behavioral analyses from 2 to 14 months of age. cGAS deletion significantly ameliorated HD-associated motor impairments, as evidenced by improved rotarod performance, enhanced coordination on beam walk, and better outcomes across a comprehensive behavioral battery. It also mitigated the progressive body-weight loss characteristic of zQ175 mice. Analysis of brain sections further revealed that cGAS deletion reduced the enlargement of lateral ventricles and attenuated both astrogliosis and microgliosis in the striatum. While cGAS loss produced minimal effects in wild-type littermates, transcriptomic profiling of HD brains showed downregulation of genes associated with development and cell–cell communication (Mid1-ps1, Slc45a3, Ilvbl, Col5a3) and upregulation of transcripts linked to ion transport and synaptic activity (Pgam2, Nos1, Cort, RasGef1a). Targeted lipidomics uncovered elevated levels of bioactive immunoregulatory lipids—particularly 12-HETE (ω-6) and 12-HEPE (ω-3)—in HD mice lacking cGAS. Finally, to assess therapeutic potential of cGAS-STING pathway, we pharmacologically inhibited STING using H-151 in zQ175 mice, which led to improved age-dependent motor performance. Collectively, these findings identify cGAS as a critical contributor to HD pathogenesis and support cGAS–STING pathway inhibition as a promising therapeutic avenue for Huntington disease.
2025-12-13 | GSE313178 | GEO
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