Resolution of SARS-CoV-2 infection in human lung tissues is driven by extravascular CD163+ monocytes.
Devin KenneyAoife K O'ConnellAnna E TsengJacquelyn TurcinovicMeagan L SheehanAdam D NitidoPaige MontanaroHans P GertjeMaria EricssonJohn H ConnorVladimir VrbanacNicholas A CrosslandChristelle HarlyAlejandro B BalazsFlorian DouamPublished in: bioRxiv : the preprint server for biology (2024)
The lung-resident immune mechanisms driving resolution of SARS-CoV-2 infection in humans remain elusive. Using mice co-engrafted with a genetically matched 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 infection is rapidly cleared from fLX following a peak of viral replication. Acute replication results in the emergence of cell subsets enriched in viral RNA, including extravascular inflammatory monocytes (iMO) and macrophage-like T-cells, which dissipate upon infection resolution. iMO display robust antiviral responses, are transcriptomically unique among myeloid lineages, and their emergence associates with the recruitment of circulating CD4+ monocytes. Consistently, mice depleted for human CD4+ cells but not CD3+ T-cells failed to robustly clear infectious viruses and displayed signatures of chronic infection. Our findings uncover the transient differentiation of extravascular iMO from CD4+ monocytes as a major hallmark of SARS-CoV-2 infection resolution and open avenues for unravelling viral and host adaptations defining persistently active SARS-CoV-2 infection.
Keyphrases
- respiratory syndrome coronavirus
- sars cov
- dendritic cells
- peripheral blood
- single molecule
- endothelial cells
- gene expression
- nk cells
- induced apoptosis
- bone marrow
- oxidative stress
- induced pluripotent stem cells
- single cell
- metabolic syndrome
- liver failure
- cell therapy
- stem cells
- drug induced
- pluripotent stem cells
- genome wide
- mesenchymal stem cells
- cell cycle arrest
- immune response
- endoplasmic reticulum stress
- signaling pathway
- blood brain barrier
- skeletal muscle
- wild type
- hepatitis b virus
- mechanical ventilation