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Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses

  1. Author:
    Hartmann, Jordan A
    Cardoso, Marcella R
    Talarico, Maria Cecilia Ramiro
    Kenney, Devin J
    Leone, Madison R
    Reese, Dagny C
    Turcinovic, Jacquelyn
    O'Connell, Aoife K
    Gertje, Hans P
    Marino, Caitlin
    Ojeda, Pedro E
    De Paula, Erich V
    Orsi, Fernanda A
    Velloso, Licio Augusto
    Cafiero, Thomas R
    Connor, John H
    Ploss, Alexander
    Hoelzemer, Angelique
    Carrington,Mary
    Barczak, Amy K
    Crossland, Nicholas A
    Douam, Florian
    Boucau, Julie
    Garcia-Beltran, Wilfredo F

  2. Author Address

    Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA., Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA., Department of Virology, Immunology, and Microbiology, Chobanian and Avedisian Boston University School of Medicine, Boston, MA, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA., School of Medical Sciences, University of Campinas, Campinas, SP, Brazil; Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil., School of Medical Sciences, University of Campinas, Campinas, SP, Brazil; Obesity and Comorbidities Research Center, University of Campinas, Campinas, SP, Brazil., Department of Molecular Biology, Princeton University, Princeton, NJ, USA., First Department of Medicine, Division of Infectious Diseases, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; Institute for Infection and Vaccine Development (IIRVD), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; Research Department Virus Immunology, Leibniz Institute for Virology, Hamburg, Germany., Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Department of Virology, Immunology, and Microbiology, Chobanian and Avedisian Boston University School of Medicine, Boston, MA, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA. Electronic address: jboucau@mgh.harvard.edu., Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. Electronic address: wgarciabeltran@mgh.harvard.edu.,
    1. Year: 2024
    2. Date: Apr 11
    3. Epub Date: 2024 04 11
  2. Journal: Cell
  4. Type of Article: Article
  1. Abstract:

    SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy. Copyright © 2024 Elsevier Inc. All rights reserved.

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External Sources

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  2. DOI: 10.1016/j.cell.2024.03.026
  3. PMID: 38653235
  4. PII : S0092-8674(24)00317-9

Library Notes

  1. Fiscal Year: FY2023-2024
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