SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes

Shi, Chong-Shan; Nabar, Neel R.; Huang, Ning-Na; Kehrl, John H.

Finally, RNA or DNA virus infection is known to trigger NLRP3 or AIM2 inflammasome activation 43, 44 . The released IL-1β and IL-18 functions to promote host defense, but aberrant inflammasome activation can result in excessive inflammation and enhanced disease. Examples include the influenza encoded proton-selective ion channel M2 which provides signal 2 for NLRP3 inflammasome activation 45 , the encephalomyocarditis virus viroporin 2B which promotes the release of intracellular Ca 2+ from intracellular stores also providing signal 2 46 , and the pathogenic influenza A viruses which use PB1-F2 to activate NLRP3 inflammasomes 47 . Our findings indicate the SARS-CoV can activate NLRP3 inflammasome in macrophages via ORF8b. While SARS-CoV abortively infects macrophages/monocytes, enough ORF8b may be present to impact lysosome integrity, autophagy pathways, and NLRP3 inflammasomes. In contrast to macrophages, the SARS-CoV productively replicates in lung epithelial cells. These cells also express NLRP3 and can assemble NLRP3 inflammasomes. In humans infected with the SARS-CoV the full impact of ORF-8b on the pathways we delineated in this study are likely in the lung epithelium. ORF8b may contribute to the cytokine storm and inflammasome activation that occurs during severe SARS-CoV infection. Moving forward, live virus deletion studies are required to assess the effects of ORF8b mediated intracellular aggregates and ORF8b mediated NLRP3 activation. However, here we identify novel mechanisms through which ORF8b may contribute to SARS pathogenesis.