Resolution of SARS-CoV-2 infection in human lung tissues is driven by CD163+ inflammatory monocytes (scRNA-Seq)

The lung-resident immune mechanisms driving resolution of SARS-CoV-2 infection in humans remain elusive due to limitations associated with human studies. Using mice co-engrafted with a human immune system and fetal lung xenograft (fLX), we mapped the immunological events defining resolution of SARS-CoV-2 infection in human lung tissues. Viral particles and RNA are rapidly cleared from fLX following a peak of viral replication. Clearance is associated with the emergence of a short-lived inflammatory monocyte (iMO) and a macrophage-like T-cell subset enriched in viral RNA. iMO exhibit an exclusive antiviral response, and the upregulation of monocyte chemoattractive signals by infected fLX underscores a link between circulating CD4+ monocyte recruitment and iMO differentiation. Consistently, mice systemically depleted for human CD4+ cells but not for CD3+ T-cells fail to robustly clear infection and display signatures of chronic infection. Our findings uncover iMO differentiation as a critical hallmark of successful resolution of SARS-CoV-2 infection in human lung tissues, and open avenues to understand the drivers of persistently active SARS-CoV-2 infection.