JOURNAL OF IMMUNOLOGY
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2024
·Vol. 212
·期 7
·1188-1195
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IF 3.6
Li Qizhao,Jia Mutian,Song Hui,Peng Jun,Zhao Wei,Zhang Weifang
STING-mediated DNA sensing pathway plays a crucial role in the innate antiviral immune responses. Clarifying its regulatory mechanism and searching STING agonists has potential clinical implications. Although multiple STING agonists have been developed to target cancer, there are few for the treatment of infectious diseases. Astaxanthin, a natural and powerful antioxidant, serves many biological functions and as a potential candidate drug for many diseases. However, how astaxanthin combats viruses and whether astaxanthin regulates the cyclic GMP-AMP synthase–STING pathway remains unclear. In this study, we showed that astaxanthin markedly inhibited HSV-1–induced lipid peroxidation and inflammatory responses and enhanced the induction of type I IFN in C57BL/6J mice and mouse primary peritoneal macrophages. Mechanistically, astaxanthin inhibited HSV-1 infection and oxidative stress-induced STING carbonylation and consequently promoted STING translocation to the Golgi apparatus and oligomerization, which activated STING-dependent host defenses. Thus, our study reveals that astaxanthin displays a strong antiviral activity by targeting STING, suggesting that astaxanthin might be a promising STING agonist and a therapeutic target for viral infectious diseases.
研究领域:
免疫学
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病毒学
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药理学
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DOI
PubMed
高影响因子
Communications Biology
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2024
·Vol. 7
·期 1
·1-11
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IF 5.2
Qin Danhui,Song Hui,Wang Caiwei,Ma Xiaojie,Fu Yu,Zhao Chunyuan,Zhao Wei,Zhang Lei,Zhang Weifang
Stimulator of interferon genes (STING) is vital in the cytosolic DNA-sensing process and critical for initiating the innate immune response, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases. Zinc finger CCCH-type antiviral protein 1 (ZC3HAV1) specifically binds the CpG dinucleotides in the viral RNAs of multiple viruses and promotes their degradation. ZAPS (ZC3HAV1 short isoform) is a potent stimulator of retinoid acid-inducible gene I (RIG-I) signaling during the antiviral response. However, how ZC3HAV1 controls STING signaling is unclear. Here, we show that ZC3HAV1 specifically potentiates STING activation by associating with STING to promote its oligomerization and translocation from the endoplasmic reticulum (ER) to the Golgi, which facilitates activation of IRF3 and NF-κB pathway. Accordingly, Zc3hav1 deficiency protects mice against herpes simplex virus-1 (HSV-1) infection- or 5,6-dimethylxanthenone-4-acetic acid (DMXAA)-induced inflammation in a STING-dependent manner. These results indicate that ZC3HAV1 is a key regulator of STING signaling, which suggests its possible use as a therapeutic target for STING-dependent inflammation.
研究领域:
免疫学
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病毒学
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炎症性疾病
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DOI
PubMed
高影响因子
Nano Today
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2023
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IF 17.4
Jingjing Hu,Xujiao Zhou,Sijia Chen,Di Yin,Yuhan Yang,Minjie Chen,Chunyi Gui,Yujia Cai,Jiaxu Hong,Yiyun Cheng
Herpes simplex keratitis (HSK) caused by herpes simplex virus-1 infection of the cornea has taken a significant toll on the visual health of people worldwide. Anti-viral hydrogels are preferred in the treatment of HSK due to enhanced topical drug retention and reduced side effects, however, current polymer-based gelling systems usually generate clumpy or uneven gel layers on ocular surface, and are easily cleared by eyelid blinking. This study proposes a supramolecular gel co-assembled by all-small-molecule building blocks including ganciclovir and 2′-deoxyguanosine in the presence of potassium ions . The developed gel performs fascinating rheological and texture properties including high viscoelastic, good spread ability, and deformation recovery behavior, enabling the formation of a uniform and thin gel layer on ocular surface to resist the clearance by eyelid blinking and tear washing. The gel shows similar ocular convenience, but much longer drug retention in ocular tissues and higher therapeutic efficacy compared to the clinical ganciclovir gel on the primary and recurrent mouse HSK models, rabbit HSK models, and also efficiently inhibited the HSV-1 replication in ex vivo human corneal tissues . The results suggest that this all-small-molecule supramolecular gel could be a promising drug formulation for treating HSK. Data and materials availability The main data supporting the results in this study are available within the paper and its Supplementary Information . The associated raw data and analyzed datasets are too large to be readily shared publicly, but they are available from the corresponding author on reasonable request.
研究领域:
药剂学
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病毒学
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眼科学
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材料科学
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DOI
高影响因子
NANOTECHNOLOGY
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2024
·Vol. 36
·期 6
·065101
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IF 2.9
Xu Chen,Jian Yue,Xiongjun Xu,Jiajun Chen,Xuechan Huang,Yukai Huang,Yang Yang,Feng Li,Tianwang Li
Selenium-based nanoparticles exhibit antiviral activity by directly modulating immune function. Despite recent promising developments in utilizing selenium nanoparticles (Se NPs) against viral infections, the impact of surface ligand charge on the conformation and interaction with viral proteins, as well as the effectiveness of Se NPs in anti-Herpes simplex virus 1 (HSV-1) infection remains unexplored. In this study, three types of selenium nanoparticles (CTAB-Se, PVP-Se, SDS-Se) with distinct surface charges were synthesized by modifying the surface ligands. We found that apart from differences in surface charge, the size, morphology, and crystal structure of the three types of Se NPs were similar. Notably, although the lipophilicity and cellular uptake of SDS-Se with a negative charge were lower compared to positively charged CTAB-Se and neutrally charged PVP-Se, SDS-Se exhibited the strongest protein binding force during interaction with HSV-1. Consequently, SDS-Se demonstrated the most potent anti-HSV-1 activity and safeguarded normal cells from damage. The mechanistic investigation further revealed that SDS-Se NPs effectively inhibited the proliferation and assembly of HSV-1 by powerfully suppressing the key genes and proteins of HSV-1 at various stages of viral development. Hence, this study highlights the significant role of surface ligand engineering in the antiviral activity of Se NPs, presenting a viable approach for synthesizing Se NPs with tailored antiviral properties by modulating surface charge. This method holds promise for advancing research on the antiviral capabilities of Se NPs.
研究领域:
纳米技术
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病毒学
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材料科学
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免疫学
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药学
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产品关联
DOI
PubMed
高影响因子
IMMUNITY
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2025
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IF 26.3
Zhimeng Wang,Yanfei Hou,Peiyuan Liu,Ruinan Wu,Jiaming Yang,Shilong Fan,Zexu Peng,Xiaoxu Han,Bin Su,Conggang Zhang
The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-cyclic GMP-AMP (cGAMP)-stimulator of interferon genes (STING) pathway mediates antiviral innate immunity upon sensing cytosolic DNA. Here, we examined the impact of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a paralog of the LXR lipid metabolism-induced cGAMP-degrading enzyme SMPDL3A, on viral infection. We found that SMPDL3B was induced and stabilized by both viral infection and membrane-disturbing agents, suggesting a role in sensing membrane stress as an early signal of cellular danger. Deletion of SMPDL3B impaired DNA virus infection. Upon induction, SMPDL3B suppressed cGAS-STING signaling and downstream transcriptional pathways, including the interferon response. Mechanistically, SMPDL3B functioned as a cGAMP hydrolase; cGAMP-induced SMPDL3B dimerization enabled its hydrolase activity and a negative feedback loop that dampened STING signaling. SMPDL3B-deficient cells had elevated cGAMP concentrations, and Smpdl3b −/− mice exhibited enhanced cGAMP accumulation, heightened immune activation, and reduced viral loads upon herpes simplex virus type 1 (HSV-1) infection. Thus, SMPDL3B links membrane stress to modulation of cGAS-STING signaling through cGAMP degradation, with potential implications in the contexts of inflammation or autoimmunity.
研究领域:
免疫学
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病毒学
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细胞生物学
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先天免疫
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信号转导
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2024
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IF 6.7
Ziwei Huang,Shan Li,Lishan Zhong,Yuan Su,Menghe Li,Xiaohui Wang,Zexu Wang,Zhiping Wang,Cuifang Ye,Zhe Ren,Xiao Wang,Qiongzhen Zeng,Kai Zheng,Yifei Wang
Background Herpes simplex virus type 1 (HSV-1)-induced herpes simplex encephalitis (HSE) has a high mortality rate in clinically immunocompromised patients, while recovered patients often experience neurological sequelae due to neuroinflammation. Nucleoside drugs and nucleoside analogues such as acyclovir and ganciclovir are mainly used in clinical treatment, and the emergence of resistant viral strains makes the development of new anti-herpesvirus encephalitis drugs urgent. Resveratrol is a multifunctional, plant-derived bioactive compound and its antiviral potential is attracting much attention. Purpose This study aimed to investigate the anti-HSV-1 mechanism of resveratrol in microglial cells and in the HSE mouse model. Methods The antiviral effect of resveratrol on HSV-1 infection was investigated by plaque assay, virus titer, immunofluorescence, Western blot and time-of-addition assay. The influence of resveratrol on stimulator of interferon gene (STING)/Nuclear Factor kappa B (NF-κB) signaling pathway-mediated neuroinflammation was examined by Western blot, RT-qPCR and ELISA. The interaction between resveratrol and STING/heat shock protein 90 beta (HSP90β) was evaluated by molecular modeling, co-immunoprecipitation, and drug affinity responsive target stability assay. The therapeutic effect of resveratrol on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. Results Resveratrol inhibited the early process of HSV-1 infection, and interfered with the STING/NF-κB signaling pathway to attenuate HSV-1-induced neuroinflammation and microglial M1 polarization, independent of its classical target Sirtuin1. Mechanistically, resveratrol completely bound to Glu515 and Lys491 of HSP90β, thus disrupting the HSP90β-STING interaction and promoting STING degradation. Resveratrol also significantly alleviated viral encephalitis and neuroinflammation caused by HSV-1 in the HSE mouse model. Conclusion Resveratrol acted as a non-classical HSP90β inhibitor, binding to the STING-HSP90β interaction site to promote STING degradation and attenuate HSV-1-induced encephalitis and neuroinflammation. These findings suggest the alternative strategy of targeting HSP90β and resveratrol-mediated inhibition of HSP90β as a potential antiviral approach.
研究领域:
病毒学
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神经科学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
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