VETERINARY MICROBIOLOGY
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2023
·
IF 3.3
Lujie Zhang,Xing Liu,Jian Mao,Yangyang Sun,Yanni Gao,Juan Bai,Ping Jiang
Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important causative agents in the pig industry worldwide, causing reproductive failure in sows and respiratory problems in growing pigs. Glucose metabolism is a major pathway for energy production and interacts with many cellular processes, such as innate immunity response. It is unclear whether PRRSV infection can use the glucose metabolic pathway to generate immune escape in favor of viral replication. Here, we found that high glucose promotes PRRSV replication and glycolysis, and inhibits poly(I:C)-induced RLR signaling. Conversely, inhibition of the glycolysis pathway significantly promoted poly(I:C)-induced RLR signaling and inhibited PRRSV replication, suggesting that glycolysis promotes PRRSV replication by inhibiting interferon signaling. Furthermore, PRRSV promotes glycolysis to produce lactate, which acts as a key metabolite to promote viral replication by inhibiting RLR signaling by targeting MAVS. And the glycolytic inhibitors targeting HK2 and LDHA in glycolysis could inhibit PRRSV replication. Taken together, these findings suggested that PRRSV infection promotes glycolysis to produce lactate, which targets MAVS to inhibit RLR signaling and thus promote viral replication. Our findings provide an insight into the pathogenesis of PRRSV and offer a theoretical basis for further development of antiviral therapeutic targets.
研究领域:
病毒学
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免疫学
·
分子生物学
·
细胞代谢
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PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 1
·
IF 6.9
Hanli Guo,Minghui Sun,Mengdie Tao,Juanjuan Zhu,Yulu Song,Saihua Chen,Zhaoxi Guo,Xiang Zhang,Fajian Hou,Chunmeng Sun,Xiaonan Ma,Haiyang Hu,Ze Hong,Chen Wang
Osteoarthritis (OA) is a prevalent age-related joint disorder with limited treatment options. Chronic activation of the innate immune response in chondrocytes plays a key role in OA progression. However, the underlying mechanisms remain incompletely understood. Here, we report that mitochondrial antiviral signaling protein (MAVS) exacerbates cartilage extracellular matrix (ECM) degradation in OA. MAVS activation is observed in chondrocytes from both OA patients and the destabilization of the medial meniscus (DMM) mouse model. Both constitutive and chondrocyte-specific MAVS knockout alleviate cartilage degradation, osteophyte formation, subchondral bone remodeling, and synovitis in DMM mice. Conversely, MAVS overexpression aggravates these OA phenotypes. Mechanistically, cytosolic accumulation of mitochondrial double-stranded RNA in chondrocytes triggers MAVS activation, leading to MAVS-nuclear factor κB-dependent ECM degradation by inducing matrix metalloproteinase 3 (MMP3) and MMP13. Pharmacologically blocking MAVS using L-lactate significantly attenuates ECM degradation and OA progression. These findings suggest that MAVS signaling is critical in OA pathogenesis and may be a potential therapeutic target for OA treatment.
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Molecular Medicine Reports
·
2025
·Vol. 32
·期 3
·1-12
·
IF 3.5
Kaixiang Zhao,Shaochen Wang,Dandan Feng,Dongwei Wang,Guang Yang,Fangfang Lang
The specific mechanisms of doxorubicin (Dox)‑induced cardiotoxicity (DIC) remain unclear. In the present study, H9c2 cardiomyocytes were treated with Dox, and it was revealed that DEAD‑box RNA helicase 3 X‑linked (DDX3X), mitochondrial antiviral signaling (MAVS) and stress granules (SGs) were present at lower levels in the treated H9c2 cardiomyocytes compared with those in the control cells. The present study further investigated the mechanisms through which DIC occurs. Pretreatment with arsenite, which pharmacologically accelerates SGs, alleviated the myocardial injury caused by Dox. By contrast, anisomycin, an SG inhibitor, increased cardiomyocyte apoptosis induced by Dox. In addition, both DDX3X knockdown and pretreatment with RK‑33 (a DDX3X pharmacological inhibitor) decreased SG expression, whereas DDX3X overexpression promoted SG generation. These results indicated that DDX3X mitigated DIC through the regulation of SGs. In addition, MAVS knockdown inhibited SG assembly and reduced the expression of the anti‑apoptotic inhibitor Bcl2, and MAVS was influenced by DDX3X, thereby serving as a connector between DDX3X and SGs. The results from western blotting, reverse transcription‑quantitative PCR, immunofluorescence and flow cytometry analysis demonstrated that DDX3X, MAVS, and SGs may serve as key protective factors in DIC.
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Cell Reports
·
2026
·Vol. 45
·期 8
·
IF 7.7
Jing Wu,Zihan Chen,Shengxiang Yin,Yunqiang Chen,Tianxin Zhang,Yaoyao Gao,Yanfei Wei,Yuhua Liu,Fangji Yang,Ling Sang,Xuesong Liu,Yongxiang Liu,Wenting Zhu,Yuheng Shi,Nan Qi
Dysregulation of innate immunity during respiratory RNA virus infections drives systemic hyperinflammation and lung injury. Here, we show that importin β4 (IPO4) has a role in inhibiting antiviral innate immunity. Transcriptomics analysis illustrated a downregulation of IPO4 in alveolar macrophages, lung ciliated epithelium, and peripheral blood mononuclear cells from severely ill patients with COVID-19 or influenza. We further identified CCAAT/enhancer-binding protein beta (CEBPB) as the transcription factor for IPO4 reduction during RNA viral infections. Loss-of-function validation demonstrated that IPO4 dampens the innate antiviral and inflammatory responses in vitro and in vivo . Mechanistically, IPO4 sequesters fatty acid synthase (FASN) to block palmitic acid production, thereby inhibiting mitochondrial antiviral signaling protein (MAVS) activation and the downstream innate immune signaling. Moreover, Adeno-associated virus (AAV)-mediated pulmonary restoration of IPO4 significantly alleviated viral pneumonia in mice. These results indicate that the CEBPB-IPO4-FASN-MAVS axis preserves innate immune homeostasis to avoid inflammatory pathology, highlighting IPO4 as a potential therapeutic target for severe viral pneumonia.
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Frontiers in Pharmacology
·
2019
·
IF 3.845
Luo Zhuo,Liu Li-Fang,Wang Xiao-Hua,Li Wen,Jie Chong,Chen Huan,Wei Fan-Qin,Lu Dan-Hua,Yan Chang-Yu,Liu Bo,Kurihara Hiroshi,Li Yi-Fang,He Rong-Rong
Stress has been proven to modulate an individual’s immune system through the release of pituitary and adrenal hormones such as the catecholamines, growth hormone, and glucocorticoids. These signal molecules can significantly alter the host immune system and make it susceptible to viral infection. In this study, we investigate whether epigoitrin, a natural alkaloid from Isatis indigotica, provides protection against influenza infection by reducing the host’s susceptibility to influenza virus under stress and its underlying mechanism. To support it, the mouse restraint stress model and the corticosterone-induced stress model were employed. Our results demonstrated that epigoitrin significantly decreased the susceptibility of restraint mice to influenza virus, evidenced by lowered mortality, attenuated inflammation, and decreased viral replications in lungs. Further results revealed that epigoitrin reduced the protein expression of mitofusin-2 (MFN2), which elevated mitochondria antiviral signaling (MAVS) protein expression and subsequently increased the production of IFN-β and interferon inducible transmembrane 3 (IFITM3), thereby helping to fight viral infections. In conclusion, our study indicated that epigoitrin could reduce the susceptibility to influenza virus via mitochondrial antiviral signaling.
研究领域:
免疫学
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病毒学
·
药理学
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Frontiers in Microbiology
·
2025
·
IF 4.5
Di Zeng,Huifen Zhou,Haitong Wan,Jing Chen
Objective: Derived from Ma Huang Decoction in the Shang Han Lun, Yinhua Pinggan Granules (YHPG) are used in traditional Chinese medicine for treating influenza. This study highlights the gut microbiota’s role in intestinal damage and acute lung injury from influenza virus infection, offering insights into influenza A virus prevention and treatment through the gut-lung axis.Methods: Using a mouse model disrupted by a four-antibiotic regimen, we assessed survival, weight, lung, and spleen indices post-IAV infection. We evaluated lung and intestinal pathology, viral load, and protein expressions via H&E staining, RT-qPCR, and immunofluorescence. 16S rRNA sequencing and targeted metabolomics were utilized to uncover the impact of YHPG treatment on disrupted gut microbiota and its metabolites after H1N1 infection.Results: H&E staining showed severe lung and intestinal damage in IAV-infected mice with disrupted gut microbiota. Immunofluorescence results demonstrated that relative depletion of gut microbiota might exacerbate colonic barrier damage in IAV-infected mice. YHPG restored microbiota diversity, increasing SCFA-producing bacteria, aligning with metabolite changes. Western blot and RT-qPCR showed activation of the GPR43-MAVS-IRF3-IFN-I pathway, linked to SCFA regulation.Conclusion: YHPG alleviate influenza symptoms, promoting SCFA-producing bacteria and maintaining gut homeostasis. They modulate the GPR43-MAVS-IRF3-IFN-β pathway, suggesting novel treatment avenues for influenza through gut microbiota modulation.
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高影响因子
ARCHIVES OF VIROLOGY
·
2024
·Vol. 169
·期 11
·1-10
·
IF 2.5
Jiao Qian,Zhu Shu,Liao Baolin,Liu Huiyuan,Guo Xiaoyan,Wu Lina,Chen Chuming,Peng Liang,Xie Chan
NLR family member X1 (NLRX1) is an important member of the NOD-like receptor (NLR) family and plays unique roles in immune system regulation. Patients with hepatitis B virus (HBV) infection are more likely to have the NLRX1 mutation p.Arg707Cys than healthy individuals. It has been reported that NLRX1 increases the infection rate of HBV in HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP). However, the role of NLRX1 mutation ( p.Arg707Cys ) in hepatitis remains unclear. We constructed Huh7 cells that stably overexpressed NTCP, using LV003 lentivirus. First, wild-type (WT) and mutant (MT) NLRX1 overexpression plasmids were constructed. The MT plasmid contained a point mutation at position 707 of the WT overexpression plasmid. Then, Huh7-NTCP cells were transfected with the WT or MT NLRX1 overexpression plasmid, and subsequent NLRX1 expression was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. HBV RNA levels were determined using RT-qPCR. HBsAg and HBcAg levels were confirmed immunohistochemically. Interferon alpha (IFN-α), interleukin 6 (IL-6), and type I interferon beta (IFN-β) levels were determined using enzyme-linked immunosorbent assay kits. p-p65, p-interferon regulatory factor (IRF) 3, and p-IRF7 expression levels were examined using western blot. The interaction of NLRX1 and retinoic acid-inducible gene (RIG)-1/mitochondrial antiviral signaling (MAVS) protein was confirmed by coimmunoprecipitation. The interaction of NLRX1 with IFN-α, IL-6, or IFN-β was analyzed by dual luciferase reporter gene assay. The levels of HBV RNA, HBsAg, and HBcAg in infected cells transfected with the WT NLRX1 or MT NLRX1 expression plasmid were higher than those in the untransfected control group; and these levels were lower in the cells transfected with MT NLRX1 than in those transfected with WT NLRX1. The levels of IFN-α, IFN-β, IL-6, p-p65, p-IRF3, and p-IRF7 were lower in cells transfected with WT NLRX1 or MT NLRX1 than in control cells. The levels of IFN-β, p-p65, p-IRF3, and p-IRF7 were higher in cells transfected with MT NLRX1 than in those transfected with WT NLRX1. Moreover, NLRX1 competitively inhibited RIG1 binding to MAVS, but the mutation in MT NLRX1 reduced this inhibitory effect. In addition, NLRX1 decreased the promoter activity of IFN-α, IFN-β, and IL-6. Our findings revealed that NLRX1 is a regulatory factor that inhibits the anti-HBV ability of hepatocytes and that the mutation p.Arg707Cys in NLRX1 suppresses HBV infection and activates the IFN/nuclear factor κB pathway.
研究领域:
免疫学
·
病毒学
·
分子生物学
·
细胞生物学
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