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.

Though the exact mechanistic role of ORF8b in SARS-CoV pathogenesis remains unclear, it is well established that the splitting of ORF8 corresponds with the shift from the early to the middle stage of the SARS epidemic, with the majority of affected patients being infected by virus containing the split ORF 36 . Recent advances in mouse models have shown that SARS pathogenesis is driven by high initial virus titers resulting from a late interferon response, which drives aberrant recruitment of IMMs and activation of the innate immune response resulting in cytotoxicity 9 . Given the likelihood that ORF8b is evolutionarily adaptive for the virus 10 , it follows that ORF8b may contribute to SARS-CoV pathogenesis by impairing the host interferon response and/or targeting the innate immune system. While the former has been previously shown 13 , here we show that ORF8b activates intracellular stress pathways upon forming insoluble aggregates and directly targets innate immunity by activation of the NLRP3 inflammasome.