SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release

Abstract

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 100 million people and caused more than 2 million deaths worldwide. Although most infected people develop mild or moderate disease, a subset of mostly older patients develop severe life-threatening disease and die. What causes severe disease and inflammation is not well understood. Severe COVID-19 is accompanied by uncontrolled inflammation with cytokine storm resembling what occurs during sepsis. The severe inflammation observed during sepsis is the result of inflammatory cell death – pyroptosis – that releases inflammatory mediators, including interleukin-1β (IL-1β), interleukin-18 (IL-18) and cellular alarmins. Monocytes are sentinel blood cells that alert the immune system to invasive infection and danger. Pyroptosis and the release of inflammatory IL-1 family cytokines relies on inflammasome activation of caspase-1 and gasdermin D (GSDMD), which forms pores in cell membranes. Here, my co-workers and I show that approximately 10% of circulating monocytes from COVID-19 patients are infected with SARS-CoV-2 and undergo pyroptosis. Signs of pyroptosis including IL-1 family cytokines and LDH in the plasma of COVID-19 patients correlate with disease severity. Both in vivo and ex vivo monocyte infection activates the NLRP3 and AIM2 inflammasomes, caspase-1, and GSDMD cleavage and re-localization to the cell membrane. Importantly, ex vivo infection of healthy donor monocytes is enhanced by anti- SARS-CoV-2 antibodies or patient plasma. Taken together, these results implicate antibody-dependent uptake of viral particles in monocyte infection, leading to inflammatory cytokine release and pyroptosis, which may be a major contributor to the cytokine release syndrome (CRS), or “cytokine storm,” seen in severe COVID-19 patients. These findings also suggest that blocking cytokine release and pyroptosis may prevent cytokine storm and severe disease.