单位：[1]Department of Anesthesiology, Peking University First Hospital, Beijing, China[2]Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain‑Machine Integration, State Key Laboratory of Brain‑Machine Intelligence, Zhejiang University, Hangzhou 311121, China[3]Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China康复医学科华中科技大学同济医学院附属同济医院[4]Department of Pharmacy, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China北京朝阳医院[5]Department of Urology, Shengjing Hospital of China Medical University, Sanhao Street 36, Shenyang 110004, Liaoning, China中国医科大学附属盛京医院中国医科大学盛京医院[6]Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
BackgroundDepression and dysosmia have been regarded as primary neurological symptoms in COVID-19 patients, the mechanism of which remains unclear. Current studies have demonstrated that the SARS-CoV-2 envelope (E) protein is a pro-inflammatory factor sensed by Toll-like receptor 2 (TLR2), suggesting the pathological feature of E protein is independent of viral infection. In this study, we aim to ascertain the role of E protein in depression, dysosmia and associated neuroinflammation in the central nervous system (CNS).MethodsDepression-like behaviors and olfactory function were observed in both female and male mice receiving intracisternal injection of E protein. Immunohistochemistry was applied in conjunction with RT-PCR to evaluate glial activation, blood-brain barrier status and mediators synthesis in the cortex, hippocampus and olfactory bulb. TLR2 was pharmacologically blocked to determine its role in E protein-related depression-like behaviors and dysosmia in mice.ResultsIntracisternal injection of E protein evoked depression-like behaviors and dysosmia in both female and male mice. Immunohistochemistry suggested that the E protein upregulated IBA1 and GFAP in the cortex, hippocampus and olfactory bulb, while ZO-1 was downregulated. Moreover, IL-1 beta, TNF-alpha, IL-6, CCL2, MMP2 and CSF1 were upregulated in both cortex and hippocampus, whereas IL-1 beta, IL-6 and CCL2 were upregulated in the olfactory bulb. Furtherly, inhibiting microglia, rather than astrocytes, alleviated depression-like behaviors and dysosmia induced by E protein. Finally, RT-PCR and immunohistochemistry suggested that TLR2 was upregulated in the cortex, hippocampus and olfactory bulb, the blocking of which mitigated depression-like behaviors and dysosmia induced by E protein.ConclusionsOur study demonstrates that envelope protein could directly induce depression-like behaviors, dysosmia, and obvious neuroinflammation in CNS. TLR2 mediated depression-like behaviors and dysosmia induced by envelope protein, which could serve as a promising therapeutic target for neurological manifestation in COVID-19 patients.
基金：
This work was supported by National High Level Hospital Clinical Research
Funding (Scientific Research Seed Fund of Peking University First Hospital):
2022SF20 (Recipient: Wenliang Su) and National High-Level Hospital Clinical
Research Funding (High-Quality Clinical Research Project of Peking University
First Hospital): 2022CR74 (Recipient: Dongliang Mu).
第一作者单位：[1]Department of Anesthesiology, Peking University First Hospital, Beijing, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Su Wenliang,Ju Jiahang,Gu Minghui,et al.SARS-CoV-2 envelope protein triggers depression-like behaviors and dysosmia via TLR2-mediated neuroinflammation in mice[J].JOURNAL OF NEUROINFLAMMATION.2023,20(1):doi:10.1186/s12974-023-02786-x.
APA：
Su, Wenliang,Ju, Jiahang,Gu, Minghui,Wang, Xinrui,Liu, Shaozhuang...&Mu, Dongliang.(2023).SARS-CoV-2 envelope protein triggers depression-like behaviors and dysosmia via TLR2-mediated neuroinflammation in mice.JOURNAL OF NEUROINFLAMMATION,20,(1)
MLA：
Su, Wenliang,et al."SARS-CoV-2 envelope protein triggers depression-like behaviors and dysosmia via TLR2-mediated neuroinflammation in mice".JOURNAL OF NEUROINFLAMMATION 20..1(2023)
医学