Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses

Matthew A. Schaller, Yamini Sharma, Zadia Dupee, Duy Nguyen, Juan Urueña, Ryan Smolchek, Julia C. Loeb, Tiago N. Machuca, John A. Lednicky, David J. Odde, Robert F. Campbell, W. Gregory Sawyer, Borna Mehrad

Research output: Contribution to journalArticlepeer-review

Abstract

Cell lines are the mainstay in understanding the biology of COVID-19 infection but do not recapitulate many of the complexities of human infection. The use of human lung tissue is one solution for the study of such novel respiratory pathogens. We hypothesized that a cryopreserved bank of human lung tissue would allow for the ex vivo study of the interindividual heterogeneity of host response to SARS-CoV-2, thus providing a bridge between studies with cell lines and studies in animal models. We generated a cryobank of tissues from 21 donors, many of whom had clinical risk factors for severe COVID-19. Cryopreserved tissues preserved 90% cell viability and contained heterogenous populations of metabolically active epithelial, endothelial, and immune cell subsets of the human lung. Samples were readily infected with HCoV-OC43 and SARS-CoV-2 and demonstrated comparable susceptibility to infection. In contrast, we observed a marked donor-dependent heterogeneity in the expression of IL6, CXCL8, and IFNB1 in response to SARS-CoV-2. Treatment of tissues with dexamethasone and the experimental drug N-hydroxycytidine suppressed viral growth in all samples, whereas chloroquine and remdesivir had no detectable effect. Metformin and sirolimus, molecules with predicted but unproven antiviral activity, each suppressed viral replication in tissues from a subset of donors. In summary, we developed a system for the ex vivo study of human SARS-CoV-2 infection using primary human lung tissue from a library of donor tissues. This model may be useful for drug screening and for understanding basic mechanisms of COVID-19 pathogenesis.

Original languageEnglish (US)
Article numbere148003
JournalJCI Insight
Volume6
Issue number18
DOIs
StatePublished - Sep 22 2021

Bibliographical note

Funding Information:
Research in the lab of MAS is funded by Merck & Co. DJO is an equity holder in BioPharma Simulation Partners. Research in the lab of WGS is funded by Merck & Co., Alcon, and Sarepta Therapeutics. The authors would like to thank Yang Zhang, in the University of Florida Department of Medicine, for statistical support. This work was funded by National Science Foundation AWD08384 and NIH R01 AI135128 and U01 EB024501. Research reported in this publication was supported by the University of Florida Clinical and Translational Science Institute, which is supported in part by the NIH National Center for Advancing Translational Sciences under award number UL1TR001427. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Funding Information:
The authors would like to thank Yang Zhang, in the University of Florida Department of Medicine, for statistical support. This work was funded by National Science Foundation AWD08384 and NIH R01 AI135128 and U01 EB024501. Research reported in this publication was supported by the University of Florida Clinical and Translational Science Institute, which is supported in part by the NIH National Center for Advancing Translational Sciences under award number UL1TR001427. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Funding Information:
lab of MAS is funded by Merck & Co. DJO is an equity holder in BioPharma Simulation Partners. Research in the lab of WGS is funded by Merck & Co., Alcon, and Sarepta Therapeutics.

Publisher Copyright:
© 2021, Schaller et al.

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