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Isogenic iPSC-derived proximal and distal lung-on-chip models reveal tissue and virus-specific immune responses in human lungs [Airway Bottom]

ABSTRACT: MPS (Micro-physiological systems) are foreseen to play a crucial role in preclinical studies, particularly for future viral pandemics. However, the development of an MPS is often hindered by the shortage of reliable cell sources, especially different organs/tissues from a single patient to compare the host immune response. Here, we developed a human airway-on-chip and an alveolus-on-chip model using induced pluripotent stem cell (iPSC)-derived isogenic lung progenitor cells. Both chips showed replication of two different respiratory viruses, SARS-CoV-2 and Influenza virus, related cellular damage, and innate immune response on-chip. We report differential immune response against SARS-CoV-2 between the proximal and distal lung on-chip models. Airway chips elicit a robust IFN-dependent immune response whereas alveolus chips exhibit a dysregulated IFN activation but a significantly upregulated chemokine pathway. On the other hand, Influenza virus infection elicits an immune response and cellular damage of higher magnitude in both chips in comparison to SARS-CoV-2. The results show potential of the iPSC-derived lung-on-chip models to rapidly understand viral pathology and screening drugs for future pandemics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247671 | GEO | 2025/03/31

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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Isogenic iPSC-derived proximal and distal lung-on-chip models reveal tissue and virus-specific immune responses in human lungs [Airway Bottom]

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