SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response.

BioRxiv : the Preprint Server for Biology
Jessie HuangDarrell N Kotton

Abstract

The most severe and fatal infections with SARS-CoV-2 result in the acute respiratory distress syndrome, a clinical phenotype of coronavirus disease 2019 (COVID-19) that is associated with virions targeting the epithelium of the distal lung, particularly the facultative progenitors of this tissue, alveolar epithelial type 2 cells (AT2s). Little is known about the initial responses of human lung alveoli to SARS-CoV-2 infection due in part to inability to access these cells from patients, particularly at early stages of disease. Here we present an in vitro human model that simulates the initial apical infection of the distal lung epithelium with SARS-CoV-2, using AT2s that have been adapted to air-liquid interface culture after their derivation from induced pluripotent stem cells (iAT2s). We find that SARS-CoV-2 induces a rapid global transcriptomic change in infected iAT2s characterized by a shift to an inflammatory phenotype predominated by the secretion of cytokines encoded by NF-kB target genes, delayed epithelial interferon responses, and rapid loss of the mature lung alveolar epithelial program. Over time, infected iAT2s exhibit cellular toxicity that can result in the death of these key alveolar facultative progenitors, as ...Continue Reading

Citations

Jan 15, 2021·Clinical Microbiology Reviews·Aleksandra SynowiecKrzysztof Pyrc
Jan 7, 2021·Stem Cell Reviews and Reports·Irma Virant-Klun, Franc Strle
Mar 28, 2021·European Journal of Clinical Pharmacology·Suzy HuijghebaertGuido Vanham

Methods Mentioned

BETA
flow cytometry
scRNA-Seq
FACS
RNA-seq

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