SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells
Nicolas Huot, Cyril Planchais, Pierre Rosenbaum, Vanessa Contreras, Béatrice Jacquelin, Caroline Petitdemange, Marzia Lazzerini, Emma Beaumont, Aurelio Orta‐Resendiz, F.A. Rey, R. Keith Reeves, Roger Le Grand, Hugo Mouquet, Michaela Müller‐Trutwin
Abstract
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence. Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection. Viral propagation in BAL macrophages occurred from cell to cell and was inhibited by interferon-γ (IFN-γ). IFN-γ production was strongest in BAL NKG2r + CD8 + T cells and NKG2A lo natural killer (NK) cells and was further increased in NKG2A lo NK cells after spike protein stimulation. However, IFN-γ production was impaired in NK cells from macaques with persisting virus. Moreover, IFN-γ also enhanced the expression of major histocompatibility complex (MHC)-E on BAL macrophages, possibly inhibiting NK cell-mediated killing. Macaques with less persisting virus mounted adaptive NK cells that escaped the MHC-E-dependent inhibition. Our findings reveal an interplay between NK cells and macrophages that regulated SARS-CoV-2 persistence in macrophages and was mediated by IFN-γ.