Cargando…
Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492301/ https://www.ncbi.nlm.nih.gov/pubmed/34357881 http://dx.doi.org/10.1172/jci.insight.148003 |
_version_ | 1784578896941809664 |
---|---|
author | Schaller, Matthew A. Sharma, Yamini Dupee, Zadia Nguyen, Duy Urueña, Juan Smolchek, Ryan Loeb, Julia C. Machuca, Tiago N. Lednicky, John A. Odde, David J. Campbell, Robert F. Sawyer, W. Gregory Mehrad, Borna |
author_facet | Schaller, Matthew A. Sharma, Yamini Dupee, Zadia Nguyen, Duy Urueña, Juan Smolchek, Ryan Loeb, Julia C. Machuca, Tiago N. Lednicky, John A. Odde, David J. Campbell, Robert F. Sawyer, W. Gregory Mehrad, Borna |
author_sort | Schaller, Matthew A. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8492301 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-84923012021-10-07 Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses Schaller, Matthew A. Sharma, Yamini Dupee, Zadia Nguyen, Duy Urueña, Juan Smolchek, Ryan Loeb, Julia C. Machuca, Tiago N. Lednicky, John A. Odde, David J. Campbell, Robert F. Sawyer, W. Gregory Mehrad, Borna JCI Insight Research Article 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. American Society for Clinical Investigation 2021-09-22 /pmc/articles/PMC8492301/ /pubmed/34357881 http://dx.doi.org/10.1172/jci.insight.148003 Text en © 2021 Schaller et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Schaller, Matthew A. Sharma, Yamini Dupee, Zadia Nguyen, Duy Urueña, Juan Smolchek, Ryan Loeb, Julia C. Machuca, Tiago N. Lednicky, John A. Odde, David J. Campbell, Robert F. Sawyer, W. Gregory Mehrad, Borna Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses |
title | Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses |
title_full | Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses |
title_fullStr | Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses |
title_full_unstemmed | Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses |
title_short | Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses |
title_sort | ex vivo sars-cov-2 infection of human lung reveals heterogeneous host defense and therapeutic responses |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492301/ https://www.ncbi.nlm.nih.gov/pubmed/34357881 http://dx.doi.org/10.1172/jci.insight.148003 |
work_keys_str_mv | AT schallermatthewa exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT sharmayamini exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT dupeezadia exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT nguyenduy exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT uruenajuan exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT smolchekryan exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT loebjuliac exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT machucatiagon exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT lednickyjohna exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT oddedavidj exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT campbellrobertf exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT sawyerwgregory exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses AT mehradborna exvivosarscov2infectionofhumanlungrevealsheterogeneoushostdefenseandtherapeuticresponses |