Modulation of the NLRP3 inflammasome by Sars-CoV-2 Envelope protein

Sci Rep. 2021 Dec 24;11(1):24432. doi: 10.1038/s41598-021-04133-7.

Abstract

Despite the initial success of some drugs and vaccines targeting COVID-19, understanding the mechanism underlying SARS-CoV-2 disease pathogenesis remains crucial for the development of further approaches to treatment. Some patients with severe Covid-19 experience a cytokine storm and display evidence of inflammasome activation leading to increased levels of IL-1β and IL-18; however, other reports have suggested reduced inflammatory responses to Sars-Cov-2. In this study we have examined the effects of the Sars-Cov-2 envelope (E) protein, a virulence factor in coronaviruses, on inflammasome activation and pulmonary inflammation. In cultured macrophages the E protein suppressed inflammasome priming and NLRP3 inflammasome activation. Similarly, in mice transfected with E protein and treated with poly(I:C) to simulate the effects of viral RNA, the E protein, in an NLRP3-dependent fashion, reduced expression of pro-IL-1β, levels of IL-1β and IL-18 in broncho-alveolar lavage fluid, and macrophage infiltration in the lung. To simulate the effects of more advanced infection, macrophages were treated with both LPS and poly(I:C). In this setting the E protein increased NLRP3 inflammasome activation in both murine and human macrophages. Thus, the Sars-Cov-2 E protein may initially suppress the host NLRP3 inflammasome response to viral RNA while potentially increasing NLRP3 inflammasome responses in the later stages of infection. Targeting the Sars-Cov-2 E protein especially in the early stages of infection may represent a novel approach to Covid-19 therapy.

Publication types

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

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid / chemistry
  • COVID-19 / pathology
  • COVID-19 / virology
  • Coronavirus Envelope Proteins / genetics
  • Coronavirus Envelope Proteins / metabolism*
  • Down-Regulation / drug effects
  • Endoplasmic Reticulum Stress
  • Humans
  • Inflammasomes / drug effects
  • Inflammasomes / metabolism*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Janus Kinases / genetics
  • Janus Kinases / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / deficiency
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Poly I-C / pharmacology
  • RNA, Viral / metabolism
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / isolation & purification
  • SARS-CoV-2 / metabolism*

Substances

  • Coronavirus Envelope Proteins
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • RNA, Viral
  • envelope protein, SARS-CoV-2
  • Janus Kinases
  • Poly I-C