中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (6): 1255-1256.doi: 10.4103/1673-5374.327333

• 观点:神经损伤修复保护与再生 • 上一篇    下一篇

SARS-CoV-2 诱导的自噬失调可能导致新型冠状病毒病的神经元功能障碍

  

  • 出版日期:2022-06-15 发布日期:2021-12-17

SARS-CoV-2-induced autophagy dysregulation may cause neuronal dysfunction in COVID-19

Madepalli K. Lakshmana*   

  1. Department of Immunology and Nano-Medicine, Alzheimer’s Disease Research Unit, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
  • Online:2022-06-15 Published:2021-12-17
  • Contact: Madepalli K. Lakshmana, PhD, mlakshma@fiu.edu.
  • Supported by:
    This work was supported by a grant from the National Institute of Health (No. 1R21AG060299) to MKL.

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摘要： Neural Regen Res：新型冠状病毒肺炎COVID-19与SARS-CoV-2及自噬失调
    尽管新型冠状病毒肺炎COVID-19主要导致急性肺损伤，导致老年人和有潜在合并症的人死亡率高，但据报道，严重的神经系统相关疾病包括脑脊液中淋巴细胞和细胞因子升高的脑膜脑炎，经常伴有病毒存在。与SARS-CoV相比，神经元可能更容易受到 SARS-CoV-2 的影响，因为该病毒已被证实在神经元细胞系中复制，并且 COVID-19 患者表现出意识模糊和头晕。大流行最令人不安的结果是重症监护分流的做法，以配给重症监护病房的稀缺资源。因此，确定病毒如何引发大规模细胞因子风暴以及体内平衡和防御机制的失败是非常关键的，以便可以快速确定基于机制的新疗法并挽救生命。与大脑和小脑不同，最新研究发现 SARS-CoV-2 在嗅觉系统和具有严重小胶质细胞增生和淋巴细胞浸润的脑干中的检出率更高。 这些发现可能解释了在 COVID-19 重症患者中常见的嗅觉障碍和自发性呼吸丧失。
    来自美国佛罗里达国际大学的Madepalli K. Lakshmana 认为COVID-19 大流行是世界范围内一个严重的持续问题，在使用疫苗接种方面取得的成功有限，但迄今为止还没有发现有效的抗病毒药物。尽管由未消化病毒蛋白和基因组材料触发的细胞因子风暴似乎是导致死亡的主要原因，但 SARS-CoV-2 引发大量细胞因子的机制尚不完全清楚。对 SARS-CoV-2 蛋白 ORF3a 的两项独立研究得出的结论是，尽管自噬体是由该蛋白诱导的，但它们的成熟最终受损，导致自噬功能障碍和炎症增强，这似乎是 SARS-CoV-2 的一个独特特征。事实上，已经证明 SARS-CoV-2 引发的不受控制的炎症与自噬缺陷之间存在显着的巧合，这表明细胞因子风暴的增加可能是由于自噬的稳态调节失败所致。目前尚不清楚自噬是否参与了 SARS-CoV-2 蛋白降解，以及 SARS-CoV-2 在感染后期与细胞因子风暴同时发生时是否通过抑制自噬体-溶酶体融合来逃避识别和降解。重要的是，自噬体-溶酶体融合抑制似乎是 SARS-CoV-2 独有的，因为 SARS-CoV 的类似 ORF3a 蛋白未能抑制。应设计针对特定细胞类型（包括神经元和小胶质细胞）感染 SARS-CoV-2 后自噬变化的时间序列的特定实验来回答这些问题。这对全世界的科学界来说可能是一个巨大的挑战。
    文章在《中国神经再生研究（英文版）》杂志2022年 6 月 6  期发表。

https://orcid.org/0000-0002-1291-4438 (Madepalli K. Lakshmana) 

Abstract: The devastating outbreak of the ongoing coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected not only the lives of almost everyone around the world but also the governments and societies as well turning into a global catastrophe. Pneumonia of unknown cause was reported in December 2019 in Wuhan, China (Zhu et al., 2020), it rapidly spread to all parts of the globe prompting World Health Organization to declare a pandemic on March 11, 2020 (Cucinotta and Vanelli, 2020). As of October 11th, 2021, 223 countries and territories have reported COVID-19 cases with a total of more than 237 million confirmed cases and more than 4.8 million confirmed deaths (World Health Organization), with the United States leading the world by the highest number of cases thus far (over 43 million infected and 703,599 deaths). Although COVID-19 results mainly in acute lung injury leading to high mortality in the elderly and people with underlying comorbidities, significant nervous system-associated morbidities including meningoencephalitis with elevated lymphocytes and cytokines in the cerebrospinal fluid frequently with viral presence are reported (Lv et al., 2021). Neurons may be more vulnerable to SARS-CoV-2 than SARS-CoV because the virus has been confirmed to replicate in neuronal cell lines (Bar-On et al., 2020) and COVID-19 patients show signs of confusion and dizziness which were rarely reported for SARS-CoV. The most troubling outcome of the pandemic is the practice of critical care triage to ration the scarce resources of intensive care units. Therefore, it is very critical to identify how the virus elicits the massive cytokine storm and the failure of homeostatic and defense mechanisms so that mechanism-based novel therapeutics may be identified quickly and lives saved.  Here, I propose that cytokine storm which is the major cause of death in COVID-19 patients may indeed be triggered by undigested viral proteins and genomic materials due to viral-induced dysfunction of the autophagy-lysosome pathway (ALP).