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Organoid modeling of lung-intrinsic immune responses to SARS-CoV-2 infection

ABSTRACT: Current study of the mechanistic underpinnings of infectious disease is limited by an absence of human in vitro model systems which recapitulate the full spectrum of epithelial and immune responses induced by host-pathogen interactions. To address this gap, we describe a holistic, three-dimensional, air-liquid interface (ALI) lung organoid method from adult tissue comprising epithelial and stromal architecture along with a full complement of resident innate and adaptive immune cells. This novel system allows the study of the intrinsic tissue-resident immune function of the lung without requiring additional immune reconstitution from lung-extrinsic sources. Using SARS-CoV-2 infection of these 3D human lung ALI organoids, we demonstrate the ability of the endogenous immune system of the lung to mount a coordinated response including cytokine production, chemotaxis, adaptive CD4+ and CD8+ T-cell responses, and antibody production. Further, this immune response is dampened by inhibitors of viral replication and augmented in vaccinated individuals. Together, we describe the successful generation of human lung organoids that preserve the diversity of stromal and tissue-resident immune populations and SARS-CoV-2 infection thereof. This en bloc system demonstrates the sufficiency of lung to independently initiate anamnestic responses without a peripheral lymphoid component, as applicable to physiologic modeling of immune responses to SARS-CoV-2 and the broad study of pulmonary disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216049 | GEO | 2023/08/08

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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Organoid modeling of lung-intrinsic immune responses to SARS-CoV-2 infection

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