A human disease model of SARS-CoV-2-induced lung injury and immune responses with a microengineered organ chip
cell biology immunology/immunity
Authors:Zhang et al.
Link to paper: https://doi.org/10.1101/2020.07.20.211789
Journal/ Pre-Print:bioRxiv preprint
Tags: Modelling, Immunology/Immunity, Cell Biology
The establishment of the first microengineered human pulmonary model of SARS-CoV-2 infection on a chip. Which provides a promising and alternative platform for COVID-19 research.
Epithelial and endothelial cells displayed distinct transcriptome responses after SARS-CoV-2 infection. Alveolar epithelial cells showed un enrichment of type I interferon (IFN-I) signalling pathway and cytokine-mediated signalling pathway, while the activation of JAK-STAT signalling pathway was observed in pulmonary microvascular endothelial cells.
Circulating immune cells play a crucial role in mediating the damage of alveolar barrier function after SARS-CoV-2 infection.
In this study, the authors created a microengineered human disease model of SARS-CoV-2 infection. They showed that this human organ on chip model closely recapitulated the human relevant lung pathophysiology and immune responses associated with COVID-19, such as viral replication in human alveolar epithelium, alveolar-capillary barrier injury, vascular dysfunction, recruitment of immune cells, and increased inflammatory cytokine release in a physiologically-relevant manner. Interestingly, alveolar epithelial and endothelial cells have a distinct role and response in the pathogenesis of COVID-19. While alveolar epithelial cells displayed strong innate immune responses and antiviral responses following viral infection, endothelial cells display a positive regulation of JAK-STAT cascade and adaptive immune response. Moreover, they found that human circulating immune cells play a key role in exacerbating inflammatory responses and the injury of alveolar-capillary-barrier induced by SARS-CoV-2. Lastly, they could validate the antiviral efficacy of remdesivir in their infected chip model.
Impact for SARS-CoV2/COVID19 research efforts
Understand the virology and/or cell biology of SARS-CoV2/COVID19:
In this study, they showed that the human alveolar epithelial cells were more susceptible to SARS-CoV-2 infection than endothelial cells. Moreover, transcriptome analysis demonstrated a distinctive response of alveolar epithelial and endothelial cells to SARS-CoV-2 infection.
Understand the immune response to SARS-CoV2/COVID19:
The study revealed the critical roles of human circulating immune cells in exacerbating inflammatory responses and mediating alveolar injury and microvascular endothelial dysfunction induced by SARS-CoV-2 at organ-level.
In vitro study (human organ on chip)
Strengths and limitations of the paper
Novelty: This work provides a proof-of-concept to establish the first human alveolus chip capable to model human lung pathophysiology and study host-immune responses to SARS-CoV-2 infection at organ level.
Standing in the field: The results obtained from this first a microengineered human pulmonary model of SARS-CoV-2 are in agreement with the published clinical results in COVID-19 patients.
Viral model used: SARS-CoV2 strain.
Translatability: This microengineered human disease model provide a promising and alternative platform for evaluating candidate drugs and repurposing approved drugs to face COVID19 pandemic.
Main limitations: The main limitation is the use of HPAEpiC which is immortalized human alveolar epithelial cells and HULEC-5a the human lung microvasculature cell line. which didn’t mimic the real human primary alveolar tissues that contains multiple types of pneumocytes.