tetano
Editor, Senior Moderator
JCI Insight
. 2021 Aug 6;148003.
doi: 10.1172/jci.insight.148003. Online ahead of print.
Ex vitro SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses
Matthew A Schaller[SUP] 1 [/SUP], Yamini Sharma[SUP] 1 [/SUP], Zadia Dupee[SUP] 1 [/SUP], Duy T Nguyen[SUP] 2 [/SUP], Juan M Urueña[SUP] 2 [/SUP], Ryan A Smolchek[SUP] 2 [/SUP], Julia C Loeb[SUP] 3 [/SUP], Tiago N Machuca[SUP] 4 [/SUP], John A Lednicky[SUP] 3 [/SUP], David J Odde[SUP] 5 [/SUP], Robert F Campbell[SUP] 6 [/SUP], W Gregory Sawyer[SUP] 2 [/SUP], Borna Mehrad[SUP] 1 [/SUP]
Affiliations
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 allows for the ex vivo study of the inter-individual heterogeneity of host response to SARS-CoV-2 infection, 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 infectable with HCoV-OC43 and SARS-CoV-2 coronaviruses, 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-CoV2 infection. 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 novel 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.
Keywords: COVID-19; Cellular immune response; Drug screens; Inflammation.
. 2021 Aug 6;148003.
doi: 10.1172/jci.insight.148003. Online ahead of print.
Ex vitro SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses
Matthew A Schaller[SUP] 1 [/SUP], Yamini Sharma[SUP] 1 [/SUP], Zadia Dupee[SUP] 1 [/SUP], Duy T Nguyen[SUP] 2 [/SUP], Juan M Urueña[SUP] 2 [/SUP], Ryan A Smolchek[SUP] 2 [/SUP], Julia C Loeb[SUP] 3 [/SUP], Tiago N Machuca[SUP] 4 [/SUP], John A Lednicky[SUP] 3 [/SUP], David J Odde[SUP] 5 [/SUP], Robert F Campbell[SUP] 6 [/SUP], W Gregory Sawyer[SUP] 2 [/SUP], Borna Mehrad[SUP] 1 [/SUP]
Affiliations
- PMID: 34357881
- DOI: 10.1172/jci.insight.148003
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 allows for the ex vivo study of the inter-individual heterogeneity of host response to SARS-CoV-2 infection, 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 infectable with HCoV-OC43 and SARS-CoV-2 coronaviruses, 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-CoV2 infection. 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 novel 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.
Keywords: COVID-19; Cellular immune response; Drug screens; Inflammation.