Human pluripotent stem cell-derived bronchial airway organoids provide insights into differential innate immune and long-term responses to SARS-CoV-2 infection in healthy and COPD.

Abstract

Respiratory infections are a major global health concern, as underscored by the COVID-19 pandemic. To better understand bronchial tissue responses to viral infection, we have developed a preclinical in vitro model mimicking the multiciliated airway epithelium, from induced pluripotent stem cell (iPSC) and cultured in an air-liquid interface (iALI). By using iPSCs reprogrammed from patients with chronic obstructive pulmonary disease (COPD), we successfully generated a fully differentiated and functional bronchial epithelium exhibiting key COPD features with goblet and basal cell hyperplasia and tissue inflammation. SARS-CoV-2 could infected and replicated for several weeks in both healthy and COPD models, with a recurrent peak at 3 days after infection. Infected iALI exhibited cilia destruction and increased mucus secretion. Innate immune response of different infected iALI reveals a differential expression of interferon-stimulated genes (ISGs) and pro-inflammatory cytokine secretion. Notably, COPD iALI displayed an earlier innate immune response to SARS-CoV-2 infection as compared to healthy iALI, suggesting a genetic susceptibility of COPD iALI towards inflammation induced by SARS-CoV-2 infection, and a less efficient response to antivirals. In conclusion, our study demonstrates that the iALI bronchial organoid model is a powerful tool for investigating bronchial tissue responses to long term respiratory viral infections, antivirals, and patients with COPD or other airway pathology. Grapical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/662440v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@9e5ef7org.highwire.dtl.DTLVardef@16ccf60org.highwire.dtl.DTLVardef@a2b29dorg.highwire.dtl.DTLVardef@17c6f14_HPS_FORMAT_FIGEXP M_FIG C_FIG HighLightsO_LIhiPSC-derived COPD airway organoids C_LIO_LISARS-CoV-2 productively infects induced pluripotent stem-cell derived bronchial organoids iALI and persisted over the long term C_LIO_LISARS-CoV-2 iALI infection results in cilia destruction, increased mucus secretion and a strong innate immune response C_LIO_LISARS-CoV-2 infection elicited a higher and earlier innate immune response in iCOPD C_LIO_LISARS-CoV-2 infection in iCOPD respond less to antivirals C_LI Short AbstractSARS-CoV-2 causes severe lower respiratory tract infection in COVID-19 patients, which can persist over time. Here, we used an in-house developed in vitro airway organoid derived from induced human pluripotent stem cells (iALI) to study SARS-CoV-2 infection over long term in healthy or COPD patients whom respiratory failure is at risk during infection. Our results show that SARS-CoV-2 infection results in high and lethal infection of bronchial epithelial cells, that persist over time, inducing mucus secretion, destruction of ciliated cells and specific cytokine release. A late innate immune response is observed in the healthy iALI, while in iCOPD, it appears earlier and stronger, suggesting a different sensing of SARS-CoV-2 in COPD patients, accompanied by a reduce sensitivity to antivirals. In conclusion, our study demonstrates that the iALI organoid model is a powerful tool for investigating bronchial tissue responses to long term respiratory viral infections, from healthy to pathologic patients.