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.
Highlights
Severe acute respiratory syndrome coronavirus (Sars-Cov)-2 infection is characterized by a strong inflammatory response, which is thought to promote organ damage and death[1]
We show in cell culture that the Sars-Cov-2 E protein suppresses the unfolded protein response (UPR) and NLRP3 inflammasome priming, leading to reduced NLRP3dependent inflammatory responses
In mice treated with poly(I:C) to simulate the effects of viral RNA, the E protein suppresses inflammasome priming, NLRP3 inflammasome activation and inflammatory cell infiltration in the lung
Summary
Severe acute respiratory syndrome coronavirus (Sars-Cov)-2 infection is characterized by a strong inflammatory response, which is thought to promote organ damage and death[1]. Infection by different RNA viruses can lead to NLRP3 inflammasome activation, which favors the host by aiding in viral clearance[15,16]. These responses depend on NLRP3 inflammasome activation in response to viral RNA and can be simulated by administration of poly(I:C)[15]. We show in cell culture that the Sars-Cov-2 E protein suppresses the unfolded protein response (UPR) and NLRP3 inflammasome priming, leading to reduced NLRP3dependent inflammatory responses. Using poly(I:C) to simulate the effects of viral RNA in vivo the E protein reduces the NLRP3 inflammatory response and decreases lung inflammation
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
