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SARS-CoV-2 envelope protein induces necroptosis and mediates inflammatory response in lung and colon cells through receptor interacting protein kinase 1

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Abstract

SARS-CoV-2 Envelope protein (E) is one of the crucial components in virus assembly and pathogenesis. The current study investigated its role in the SARS-CoV-2-mediated cell death and inflammation in lung and gastrointestinal epithelium and its effect on the gastrointestinal-lung axis. We observed that transfection of E protein increases the lysosomal pH and induces inflammation in the cell. The study utilizing Ethidium bromide/Acridine orange and Hoechst/Propidium iodide staining demonstrated necrotic cell death in E protein transfected cells. Our study revealed the role of the necroptotic marker RIPK1 in cell death. Additionally, inhibition of RIPK1 by its specific inhibitor Nec-1s exhibits recovery from cell death and inflammation manifested by reduced phosphorylation of NFκB. The E-transfected cells’ conditioned media induced inflammation with differential expression of inflammatory markers compared to direct transfection in the gastrointestinal-lung axis. In conclusion, SARS-CoV-2 E mediates inflammation and necroptosis through RIPK1, and the E-expressing cells’ secretion can modulate the gastrointestinal-lung axis. Based on the data of the present study, we believe that during severe COVID-19, necroptosis is an alternate mechanism of cell death besides ferroptosis, especially when the disease is not associated with drastic increase in serum ferritin.

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The datasets generated during and/or analysed during the current study can be availed from the corresponding author on reasonable request.

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Acknowledgements

Indian Institute of Technology Indore for providing facilities and support. We appreciate lab colleagues for their insightful discussions and advice. We appreciate the help of Mr. Pratik Kundu for his support in performing some of the experiments. We acknowledge the Indian Council of Medical Research (Grant no. BMI/12(82)/2021 and ECD/CSTPU/Adhoc/COVID-19/28/2021-22) and Central Council for Research in Ayurvedic Sciences (Grant no. 1263/2022-23) Govt. of India for funding. We are also thankful to University Grants Commission, Dept. of Biotechnology Govt. of India for fellowship to Budhadev Baral and Vaishali Saini respectively in the form of research stipend. We also acknowledge DST-FIST support project No. SR/FST/LS-I/2020/621 for providing us with different instruments.

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Authors and Affiliations

  1. Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India

    Budhadev Baral, Vaishali Saini, Akrati Tandon, Siddharth Singh, Samiksha Rele & Hem Chandra Jha

  2. Central Ayurveda Research Institute, 4-CN Block, Sector-V, Bidhannagar, Kolkata, 700091, India

    Amit Kumar Dixit

  3. School of Biotechnology, Devi Ahilya Vishwavidyalaya, Takshashila Campus, Indore, Madhya Pradesh, 452001, India

    Hamendra Singh Parmar

  4. Regional Ayurveda Research Institute, Amkhoh, Gwalior, Madhya Pradesh, 474001, India

    Ajay Kumar Meena

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Contributions

Conceptualization: HCJ and BB, methodology: HCJ and BB, formal analysis and investigation: BB, VS, AT, SS, SR, AKD, HSP and AKM, writing—original draft preparation: BB, writing—review and editing: BB, AKD, HSP, AKM and HCJ, writing—preparation of figures: BB and VS, funding acquisition: HCJ, supervision: HCJ.

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Correspondence to Hem Chandra Jha.

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Baral, B., Saini, V., Tandon, A. et al. SARS-CoV-2 envelope protein induces necroptosis and mediates inflammatory response in lung and colon cells through receptor interacting protein kinase 1. Apoptosis 28, 1596–1617 (2023). https://doi.org/10.1007/s10495-023-01883-9

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