Cell Rep . Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening

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Cell Rep


. 2021 May 19;109218.
doi: 10.1016/j.celrep.2021.109218. Online ahead of print.
Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening


Toshiki Ebisudani ¹ , Shinya Sugimoto ² , Kei Haga ³ , Akifumi Mitsuishi ¹ , Reiko Takai-Todaka ³ , Masayuki Fujii ² , Kohta Toshimitsu ² , Junko Hamamoto ⁴ , Kai Sugihara ⁴ , Tomoyuki Hishida ⁵ , Hisao Asamura ⁵ , Koichi Fukunaga ⁶ , Hiroyuki Yasuda ⁷ , Kazuhiko Katayama ⁸ , Toshiro Sato ⁹



Affiliations

• PMID: 34038715
• DOI: 10.1016/j.celrep.2021.109218

Abstract

Although the main cellular target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be alveolar cells, the absence of their tractable culture system precludes the development of a clinically relevant SARS-CoV-2 infection model. Here, we establish an efficient human alveolosphere culture method and sphere-based drug testing platform for SARS-CoV-2. Alveolospheres exhibit indolent growth in a Wnt- and R-spondin-dependent manner. Gene expression, immunofluorescence, and electron microscopy analyses reveal the presence of alveolar cells in alveolospheres. Alveolospheres express ACE2 and allow SARS-CoV-2 to propagate nearly 100,000-fold in 3 days of infection. Whereas lopinavir and nelfinavir, protease inhibitors used for the treatment of human immunodeficiency virus (HIV) infection, have a modest anti-viral effect on SARS-CoV-2, remdesivir, a nucleotide prodrug, shows an anti-viral effect at the concentration comparable with the circulating drug level. These results demonstrate the validity of the alveolosphere culture system for the development of therapeutic agents to combat SARS-CoV-2.

Keywords: COVID-19; alveolosphere; drug screening; lung; organoid; stem cell niche.