Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection

J Biol Chem. 2020 Oct 9;295(41):14040-14052. doi: 10.1074/jbc.RA120.015036. Epub 2020 Aug 6.


Coronaviruses have caused several zoonotic infections in the past two decades, leading to significant morbidity and mortality globally. Balanced regulation of cell death and inflammatory immune responses is essential to promote protection against coronavirus infection; however, the underlying mechanisms that control these processes remain to be resolved. Here we demonstrate that infection with the murine coronavirus mouse hepatitis virus (MHV) activated the NLRP3 inflammasome and inflammatory cell death in the form of PANoptosis. Deleting NLRP3 inflammasome components or the downstream cell death executioner gasdermin D (GSDMD) led to an initial reduction in cell death followed by a robust increase in the incidence of caspase-8- and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated inflammatory cell deathafter coronavirus infection. Additionally, loss of GSDMD promoted robust NLRP3 inflammasome activation. Moreover, the amounts of some cytokines released during coronavirus infection were significantly altered in the absence of GSDMD. Altogether, our findings show that inflammatory cell death, PANoptosis, is induced by coronavirus infection and that impaired NLRP3 inflammasome function or pyroptosis can lead to negative consequences for the host. These findings may have important implications for studies of coronavirus-induced disease.

Keywords: NLRP3; PANoptosis; RIPK3; RNA virus; apoptosis; caspase-1; caspase-8; coronavirus; gasdermin D; host defense; infection; infectious disease; inflammasome; mouse hepatitis virus (MHV); necroptosis; plus-stranded RNA virus; pyroptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 8 / metabolism*
  • Cells, Cultured
  • Coronavirus / physiology
  • Coronavirus Infections / metabolism
  • Coronavirus Infections / pathology
  • Coronavirus Infections / veterinary
  • Cytokines / metabolism
  • Inflammasomes / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Macrophages / cytology
  • Macrophages / metabolism
  • Macrophages / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Necroptosis
  • Phosphate-Binding Proteins / genetics
  • Phosphate-Binding Proteins / metabolism
  • Pyroptosis*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*


  • Cytokines
  • Gsdmd protein, mouse
  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Phosphate-Binding Proteins
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Caspase 8