A Novel Human Extravascular Monocyte Subset with Antiviral Functions Is Crucial for Resolving Lung Tissue Infection - Archive ouverte HAL
Article Dans Une Revue BioRxiv Année : 2024

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

Aoife O’connell
  • Fonction : Auteur
Anna Tseng
  • Fonction : Auteur
Jacquelyn Turcinovic
  • Fonction : Auteur
Maegan Sheehan
  • Fonction : Auteur
Adam Nitido
  • Fonction : Auteur
Paige Montanaro
  • Fonction : Auteur
Hans Gertje
  • Fonction : Auteur
Maria Ericsson
  • Fonction : Auteur
John Connor
Vladimir Vrbanac
  • Fonction : Auteur
Nicholas Crossland

Résumé

ABSTRACT 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. One sentence summary We identified a novel human subset of lung extravascular monocytes with antiviral functions that play a critical role in resolving SARS-CoV-2 infection from human lung tissues in an immunologically naïve context.

Dates et versions

hal-04751123 , version 1 (24-10-2024)

Identifiants

Citer

Devin Kenney, Aoife O’connell, Anna Tseng, Jacquelyn Turcinovic, Maegan Sheehan, et al.. A Novel Human Extravascular Monocyte Subset with Antiviral Functions Is Crucial for Resolving Lung Tissue Infection. BioRxiv, 2024, ⟨10.1101/2024.03.08.583965⟩. ⟨hal-04751123⟩
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