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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE255199 | GEO | 2025/02/01

REPOSITORIES: GEO

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Project description:Background: Type I interferons (IFNs) are essential to the clearance of viral diseases, in part by initiating upregulation of IFN regulated genes (IRGs). A clear distinction between genes upregulated directly by virus and genes upregulated by secondary IFN production has not been made. Here we investigated the genes regulated by IFN-a2b compared to the genes regulated by SARS-CoV infection in ferrets. Methods: We characterized early host immune responses in peripheral blood and lung necropsies of ferrets injected with IFN-a2b or infected with SARS-CoV/Tor 2 strain, using microarray analysis on the Affymetrix platform. Results: We identified a common IRG signature that was upregulated in both SARS-CoV infected ferrets as well as in ferrets injected with IFN-a2b. We also identified unique patterns of gene expression for leukocyte activation, cell adhesion and complement pathways between IFN-a2b injection and SARS-CoV infection. Conclusions: Our results define the effects of IFN-a2b on the immune system of ferrets highlighting genes regulated by IFN during SARS-CoV infection. We have shown the similarities and differences of top funcional gene groups as well as pathways that play key roles in early immune responses in ferrets in response to IFN-a2b or SARS-CoV. Key words: ferret, gene expression, SARS, interferon. Keywords: time course In experiments with IFN-a2b, for peripheral blood, 15 ferrets were randomly allocated to 3 groups: Day 0, 5 ferrets (no IFN injection), day 1, 6 ferrets (injected), and day 2, 4 ferrets (injected). For lung necropsies of injected ferrets with IFN-a2b, we used 12 ferrets in 3 groups: 4 ferrets, day 0 (no IFN injection), 4 ferrets, day 1 (injected) and 4 ferrets, day 2 (injected). Experimental groups for SARS-CoV infection was as follows: For peripheral blood, 3 and 4 ferrets for day 0 (no infection) and day 2 (infection) respectively. For lung neceropsies, a total of 9 ferrets in 3 groups, each with 3 replicates for day 0 (no infection), day 1 (infection) and day 2 (infection).

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

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