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SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy.
Liang, Shuxin; Bao, Changlei; Yang, Zi; Liu, Shiyun; Sun, Yanan; Cao, Weitao; Wang, Ting; Schwantes-An, Tae-Hwi; Choy, John S; Naidu, Samisubbu; Luo, Ang; Yin, Wenguang; Black, Stephen M; Wang, Jian; Ran, Pixin; Desai, Ankit A; Tang, Haiyang.
  • Liang S; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • Bao C; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • Yang Z; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • Liu S; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • Sun Y; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • Cao W; College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
  • Wang T; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • Schwantes-An TH; Department of Cellular Biology & Pharmacology, Herbert Wertheim College of Medicine, Miami, FL, USA.
  • Choy JS; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work and Center for Translational Science, Florida International University, Port St. Lucie, FL, USA.
  • Naidu S; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Luo A; Department of Biology, The Catholic University of America, Washington, DC, USA.
  • Yin W; Krannert Institute of Cardiology, Department of Medicine, Indiana University, Indianapolis, IN, USA.
  • Black SM; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • Wang J; College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
  • Ran P; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • Desai AA; Department of Cellular Biology & Pharmacology, Herbert Wertheim College of Medicine, Miami, FL, USA.
  • Tang H; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work and Center for Translational Science, Florida International University, Port St. Lucie, FL, USA.
Signal Transduct Target Ther ; 8(1): 108, 2023 03 09.
Article in English | MEDLINE | ID: covidwho-2268983
ABSTRACT
Cardiopulmonary complications are major drivers of mortality caused by the SARS-CoV-2 virus. Interleukin-18, an inflammasome-induced cytokine, has emerged as a novel mediator of cardiopulmonary pathologies but its regulation via SARS-CoV-2 signaling remains unknown. Based on a screening panel, IL-18 was identified amongst 19 cytokines to stratify mortality and hospitalization burden in patients hospitalized with COVID-19. Supporting clinical data, administration of SARS-CoV-2 Spike 1 (S1) glycoprotein or receptor-binding domain (RBD) proteins into human angiotensin-converting enzyme 2 (hACE2) transgenic mice induced cardiac fibrosis and dysfunction associated with higher NF-κB phosphorylation (pNF-κB) and cardiopulmonary-derived IL-18 and NLRP3 expression. IL-18 inhibition via IL-18BP resulted in decreased cardiac pNF-κB and improved cardiac fibrosis and dysfunction in S1- or RBD-exposed hACE2 mice. Through in vivo and in vitro work, both S1 and RBD proteins induced NLRP3 inflammasome and IL-18 expression by inhibiting mitophagy and increasing mitochondrial reactive oxygenation species. Enhancing mitophagy prevented Spike protein-mediated IL-18 expression. Moreover, IL-18 inhibition reduced Spike protein-mediated pNF-κB and EC permeability. Overall, the link between reduced mitophagy and inflammasome activation represents a novel mechanism during COVID-19 pathogenesis and suggests IL-18 and mitophagy as potential therapeutic targets.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Signal Transduct Target Ther Year: 2023 Document Type: Article Affiliation country: S41392-023-01368-w

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Signal Transduct Target Ther Year: 2023 Document Type: Article Affiliation country: S41392-023-01368-w