Nature https://doi.org/10.1038/s41586-022-04702-4 (2022)

Monocytes do not express ACE, the receptor for SARS-CoV-2. In Nature, Lieberman and colleagues show that a small percentage of monocytes in patients with COVID-19 are infected with SARS-CoV-2 by Fcγ receptor-mediated uptake of antibody-opsonized virus and undergo inflammatory cell death. Markers of pyroptosis (GSDMD, LDH, IL-1RA and IL-18) are increased in the plasma of patients with severe compared with mild or moderate disease, and 4–6% of monocytes in patients with severe disease show the formation of ASC specks (colocalized with NLRP3 and AIM2 specks) and undergo pyroptosis. Around 10% of blood monocytes and 8–15% of lung macrophages from patients with COVID-19 stain for nucleocapsid (N) protein. ASC specks are detected in N+ macrophages, but not in N+ epithelial and endothelial cells in the lung. Detection of subgenomic RNA indicates viral replication, but infectious virus is not detected in the culture supernatants of infected monocytes. This indicates that infected monocytes do not support viral replication, but undergo pyroptosis and can contribute to systemic inflammation.