Modeling SARS-CoV-2 infectionin vitrowith a human intestine-on-chip device

Abstract

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) has given rise to a global pandemic. The gastrointestinal symptoms of some COVID-19 patients are underestimated. There is an urgent need to develop physiologically relevant model that can accurately reflect human response to viral infection. Here, we report the creation of a biomimetic human intestine infection model on a chip system that allows to recapitulate the intestinal injury and immune response induced by SARS-CoV-2, for the first time. The microengineered intestine-on-chip device contains human intestinal epithelium (co-cultured human intestinal epithelial Caco-2 cells and mucin secreting HT-29 cells) lined in upper channel and vascular endothelium (human umbilical vein endothelial cells, HUVECs) in a parallel lower channel under fluidic flow condition, sandwiched by a porous PDMS membrane coated with extracellular matrix (ECM). At day 3 post-infection of SARS-CoV-2, the intestine epithelium showed high susceptibility to viral infection and obvious morphological changes with destruction of intestinal villus, dispersed distribution of mucus secreting cells and reduced expression of tight junction (E-cadherin), indicating the destruction of mucous layer and the integrity of intestinal barrier caused by virus. Moreover, the endothelium exhibited abnormal cell morphology with disrupted expression of adherent junction protein (VE-cadherin). Transcriptional analysis revealed the abnormal RNA and protein metabolism, as well as activated immune responses in both epithelial and endothelial cells after viral infection (e.g., up-regulated cytokine genes, TNF signaling and NF-kappa B signaling-related genes). This bioengineered in vitro model system can mirror the human relevant pathophysiology and response to viral infection at the organ level, which is not possible in existing in vitro culture systems. It may provide a promising tool to accelerate our understanding of COVID-19 and devising novel therapies.

Experimental Models of SARS-CoV-2 Infection: Possible Platforms to Study COVID-19 Pathogenesis and Potential Treatments

“…Notably, they showed distinct responses of two cell types to SARS-CoV-2 infection, including activation of the type I interferon signaling cascade in epithelium and the Janus kinase-signal transducer and activator of transcription ( JAK-STAT) signaling pathway in the endothelium. Guo et al(65) created a microengineered intestineon-a-chip device to mirror the pathophysiological features and immune responses in COVID-19. This model contains cocultured human intestinal epithelial (Caco-2) cells and mucin-secreting HT-29 cells lined in the upper channel and human umbilical vein endothelial cells in the lower channel under fluidic conditions.…”

Role of biomaterials in the diagnosis, prevention, treatment, and study of corona virus disease 2019 (COVID-19)

“…Also, microfluidic-based 3D models and organ-on-a-chip systems provide biomimetic environment with air and fluid flows typical of what normally occurs in the lung, and can be useful for studying viral infection [29]. Therefore, the development of OoC-based technology to study the response of human tissues and organs to SARS-CoV-2 is urgently needed [98].…”

“…For example, gut-on-a-chip systems represent an attractive tool to study health and disease states [99], and they can be used to study SARS-CoV-2 infection. Recently, Guo et al [98] reported the development of a SARS-CoV-2 infection in vitro using a biomimetic human intestine-on-a-chip device for studying of COVID-19. The intestine-on-a-chip device contained two parallel, cell culture microchannels, an upper epithelial cell-lined channel (co-cultured human intestinal epithelial cells and mucin secreting cells) and a lower vascular endothelial cell-lined channel separated by a thin flexible polydimethylsiloxane (PDMS) membrane which was coated with ECM.…”

Application of Cell Culture Models in Studying Viral Diseases (SARS, H1N1 Flu, MERS, COVID-19): A Review

“…To study recapitulated alveolar-capillary barrier injury and inflammatory responses of SARS-CoV-2 infection, Zhang and his co-worker created a micro-engineered alveolus chip model [54]. Similarly, to recapitulate the intestinal injury and immune response by SARS-CoV-2, Yaqiong Guo and colleagues engineered an intestine-on-chip device [55]. Besides, the microfluidic model of the human blood-brain barrier indicated that spike protein subunits of SARS-CoV-2 can affect the function of blood-brain barrier [56].…”