한빛사논문
- 조회819
Rajendra Karki1#, SangJoon Lee1#, Raghvendra Mall1, Nagakannan Pandian1, Yaqiu Wang1, Bhesh Raj Sharma1, RK Subbarao Malireddi1, Dong Yang2, Sanja Trifkovic3, Jacob A. Steele4, Jon P. Connelly4, Gella Vishwanath5, Mitnala Sasikala6, Duvvur Nageshwar Reddy7, Peter Vogel8, Shondra M. Pruett-Miller4, Richard Webby3, Colleen Beth Jonsson9, and Thirumala-Devi Kanneganti1*
1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA 2UTHSC Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN, USA 3Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA 4Center for Advanced Genome Engineering (CAGE), St. Jude Children’s Research Hospital, Memphis, TN, USA 5Institute of Pulmonary Medicine and Sleep Disorders, Continental Hospitals, Asian Institute of Gastroenterology, Hyderabad, India 6Department of Basic Science, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India 7Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India 8Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA 9Department of Microbiology, Immunology, & Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA
#Equal contribution
*Corresponding author.
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), continues to cause significant morbidity and mortality in the ongoing global pandemic. Understanding the fundamental mechanisms that govern innate immune and inflammatory responses during SARS-CoV-2 infection is critical for developing effective therapeutic strategies. While IFN-based therapies are generally expected to be beneficial during viral infection, clinical trials in COVID-19 have shown limited efficacy and potential detrimental effects of IFN treatment during SARS-CoV-2 infection. However, the underlying mechanisms responsible for this failure remain unknown. In this study, we found that IFN induced ZBP1-mediated inflammatory cell death, PANoptosis, in human and murine macrophages and in the lungs of mice infected with β-coronaviruses, including SARS-CoV-2 and mouse hepatitis virus (MHV). In patients with COVID-19, expression of the innate immune sensor ZBP1 was increased in immune cells from those who succumbed to the disease compared with those who recovered, further suggesting a link between ZBP1 and pathology. In mice, IFN-β treatment following β-coronavirus infection increased lethality, and genetic deletion of Zbp1 or its Zα domain suppressed cell death and protected the mice from IFN-mediated lethality during β-coronavirus infection. Overall, our results identify that ZBP1 induced during coronavirus infection limits the efficacy of IFN therapy by driving inflammatory cell death and lethality. Therefore, inhibiting ZBP1 activity may improve the efficacy of IFN therapy, paving the way for the development of new and critically needed therapeutics for COVID-19 as well as other infections and inflammatory conditions where IFN-mediated cell death and pathology occur.
논문정보
- Research article
- 2022년 05월 (BRIC 등록일 2022-05-23)
- 국외 연구진
- 생명과학 > 감염생물학
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