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Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which is the cause of a present global pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term three-dimensional (3D) culture technique for hAT2 cells derived from primary human lung tissue, and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and pro-inflammatory genes in infected hAT2 cells, indicating robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2, and the application of defined 3D hAT2 cultures as models for respiratory diseases.

Highlights d Driver fusion oncogenes in LADCs are generated from complex genomic rearrangements d These rearrangements are frequently copy-number balanced, resembling germline events d Fusions often arise in early decades of life, leaving long latency to diagnosis d SETD2 inactivation is cooperative with fusion oncogenes in TP53-wild-type LADCs

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Next-generation sequencing technology has enabled the comprehensive detection of genomic alterations in human somatic cells, including point mutations, chromosomal rearrangements, and structural variations (SVs). Using sophisticated bioinformatics algorithms, unbiased catalogs of SVs are emerging from thousands of human cancer genomes for the first time. Via careful examination of SV breakpoints at single-nucleotide resolution as well as local DNA copy number changes, diverse patterns of genomic rearrangements are being revealed. These “SV signatures” provide deep insight into the mutational processes that have shaped genome changes in human somatic cells. This review summarizes the characteristics of recently identified complex SVs, including chromothripsis, chromoplexy, microhomology-mediated breakage-induced replication (MMBIR), and others, to provide a holistic snapshot of the current knowledge on genomic rearrangements in somatic cells.