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

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

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 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.

Highlights

The COVID-19 pandemic has highlighted the need for improved models of infection to study host-pathogen interactions, rapidly screen potential therapeutic interventions, and study fundamental pathogenic mechanisms
Cell lines are the mainstay in understanding the biology of COVID-19 infection but do not recapitulate many of the complexities of human infection
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, providing a bridge between studies with cell lines and studies in animal models

Summary

Introduction

The COVID-19 pandemic has highlighted the need for improved models of infection to study host-pathogen interactions, rapidly screen potential therapeutic interventions, and study fundamental pathogenic mechanisms. The use of human lung tissue is one solution for the study of biology of novel respiratory pathogens: lung tissue explants capture the cellular heterogeneity within the human lung, and the use of tissues from multiple donors can allow the study of the genetic diversity found within the human population To this end, human lung organoids [1, 2] and lung-on-a-chip systems [3] can be readily infected with SARS-CoV-2. Human lung organoids [1, 2] and lung-on-a-chip systems [3] can be readily infected with SARS-CoV-2 The use of these models is limited by 2 considerations: first, there are practical constraints on repeating experiments with tissue from a given donor at a later time or performing experiments with samples from multiple donors simultaneously. The optimal solution to these problems is a repeatable and scalable in vitro system that captures the intricacies of the human lung and allows parallel testing with tissue from multiple donors in a single experiment and sequential experiments using tissue from the same donor

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Results

Conclusion