A Novel Human Extravascular Monocyte Subset with Antiviral Functions Is Crucial for Resolving Lung Tissue Infection.

Autor:	Kenney D; Department of Virology, Immunology, and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA., O'Connell AK; Department of Virology, Immunology, and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA.; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Tseng AE; Department of Virology, Immunology, and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA.; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Turcinovic J; Department of Virology, Immunology, and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA.; Bioinformatics Program, Boston University, Boston, MA, USA., Sheehan ML; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.; These authors contributed equally to the work., Nitido AD; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.; These authors contributed equally to the work., Montanaro P; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA.; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Gertje HP; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA.; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Ericsson M; Electron Microscopy Core Facility, Harvard Medical School, Boston, MA, USA., Connor JH; Department of Virology, Immunology, and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA., Vrbanac V; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Crossland NA; Department of Virology, Immunology, and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA.; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Harly C; Université de Nantes, INSERM, CNRS, CRCINA, Nantes, France.; LabEx IGO 'Immunotherapy, Graft, Oncology', Nantes, France.; These authors contributed equally to the work., Balazs AB; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.; These authors contributed equally to the work., Douam F; Department of Virology, Immunology, and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA.; These authors contributed equally to the work.; Lead contact.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 15. Date of Electronic Publication: 2024 Aug 15.
DOI:	10.1101/2024.03.08.583965
Abstrakt:	The recurring emergence of novel respiratory viruses has highlighted our poor understanding of the human immune mechanisms governing the resolution of lung infection in an immunologically naïve context. Using SARS-CoV-2 as a prototypical emerging respiratory virus, we leveraged mice co-engrafted with a genetically matched fetal lung xenograft (fLX) and a human immune system (BLT-L mice) to investigate such mechanisms. While BLT-L mice effectively resolve SARS-CoV-2 infection following acute viral replication in fLX, viral clearance is robustly abrogated through systemic depletion of CD4+, but not CD3+ or CD8+ cells, resulting in persistent infection. Leveraging single-cell transcriptomics to uncover the CD4-expressing subsets driving infection resolution, we identified a novel subset of lung extravascular inflammatory monocytes (ExiMO) with antiviral functions. ExiMO are the dominant CD163-expressing myeloid population emerging in fLX upon acute infection and derive from recruited circulating CD4+ monocytes. They are highly enriched in viral RNA and elicit a robust antiviral response before vanishing from tissues when infection resolves. Notably, systemic CD4+ cell depletion results in impaired recruitment of CD163+ cells into fLX and leads to a state of immune tolerance and chronic infection defined by the absence of ExiMO antiviral responses. Together, our study uncovers ExiMO as major sentinels driving SARS-CoV-2 infection resolution in human lung tissues without pre-existing immunity. This work expands our understanding of lung extravascular monocytes and unravels novel facets of the cellular determinants governing our vulnerability to viral respiratory pathogens. Competing Interests: The authors have declared that no conflict of interest exists.
Databáze:	MEDLINE
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