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. 2022 Mar 29;18(3):e1010432.
doi: 10.1371/journal.ppat.1010432. eCollection 2022 Mar.

Airway models in a pandemic: Suitability of models in modeling SARS-CoV-2

Andrew Teo  1   2 , Caroline Lin Lin Chua  3 , Louisa L Y Chan  1
Affiliations

Airway models in a pandemic: Suitability of models in modeling SARS-CoV-2

Andrew Teo et al. PLoS Pathog. .
No abstract available

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Conflict of interest statement

The authors have declared that no competing interests exist

Figures

Fig 1
Fig 1. A flowchart illustrates the 2D cell lines, 3D models, and animal models for the understanding of the pathogenesis of SARS-CoV-2.
(A) Most 2D models originated from both human and nonhuman origins more than half a century ago, thus may not be biological relevant. However, they are easily and readily available, hence form an important first-line model for research in a pandemic to identify potential pathways of infection, tissue tropism and to generate viral stocks for further research. (B) Human primary ALI (3D model) mimics conditions in the human airway, as basal surface of cells is submerged in liquid medium, whereas the apical surface is exposed to air. ALI models are useful to identify key target cells of infection and changes in cellular morphologies in infection, whereas more advanced lung-on-a-chip can be applied to understand the role of microvasculature in COVID-19 pathogenesis. (C) Animal models are important to identify mechanistic pathways of disease, transmissibility, and preclinical testing of therapeutics. Several models have been tested with varying degree of success. Differences in viral and host homologs render some models incompatible (e.g., wild-type mouse models vs. humanized ACE2 transgenic mouse). Though Syrian hamsters, macaques, and ferrets are susceptible to infection, often they exhibit mild–moderate pathological outcomes. Large animals including macaques and ferrets are protected against reinfection, suggesting that these could be useful models in studying humoral immunity in COVID-19. ACE2, angiotensin-converting enzyme 2; ALI, air–liquid interface; COVID-19; Coronavirus Disease 2019; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; 2D, two-dimensional; 3D, three-dimensional.
Fig 2
Fig 2. Airway organoids are 3D models that are valuable to bridge the knowledge gap between 2D cell line and animal models.
(A) Generation of airway organoids from ASCs and hPSCs. ASCs-derived airway organoids (top panel). Tissue-resident adult stem cells can be isolated from healthy individual or patients’ airway samples and differentiated into functional epithelial cell types to form bronchospheres/nasal/airway organoids and alveolospheres with the presence of mesenchymal stem cells. hPSCs-derived lung organoids (bottom panel). Differentiation of hPSCs into endoderm by activin A and then to anterior foregut spheroids through the activation and inhibition of various signaling pathways. Foregut spheroids further differentiate into lung organoids with proximal and distal-like domains that closely resemble the lung morphology and functions. Key: FGF-4 (fibroblast growth factor 4); GSK3 (glycogen synthase kinase 3); TGF-β (transforming growth factor beta 1); AEC1 (alveolar epithelial type I cells); AEC2 (alveolar epithelial type II cells); and MSC (mesenchymal stem cell). (B) Future development of next-generation airway organoids. Organoids-on-a chip allows the co-culture of multiple cell types and generation of 3D multicellular structures to better model the functional units of an organ, while replenishment of nutrients and removal of wastes can be done in a controlled manner through microfluidics system. Modification of organoids using advanced gene editing techniques such as CRISPR-Cas9 can be useful for studying virus–host interactions such as deciphering signaling pathways implicated in SARS-CoV-2 pathogenesis or identifying host proteins utilized by viruses in causing infection. Current versions of airway organoids are simplified forms of the native tissue. Incorporation of immune cells and other resident niche cells can highly enhance the biomimicry of the existing airway organoids. Created with BioRender.com. ASC, adult stem cell; hPSC, human pluripotent stem cell; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; 2D, two-dimensional; 3D, three-dimensional.
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