Organoids to Dissect Gastrointestinal Virus–Host Interactions: What Have We Learned?

Abstract

Historically, knowledge of human host–enteric pathogen interactions has been elucidated from studies using cancer cells, animal models, clinical data, and occasionally, controlled human infection models. Although much has been learned from these studies, an understanding of the complex interactions between human viruses and the human intestinal epithelium was initially limited by the lack of nontransformed culture systems, which recapitulate the relevant heterogenous cell types that comprise the intestinal villus epithelium. New investigations using multicellular, physiologically active, organotypic cultures produced from intestinal stem cells isolated from biopsies or surgical specimens provide an exciting new avenue for understanding human specific pathogens and revealing previously unknown host–microbe interactions that affect replication and outcomes of human infections. Here, we summarize recent biologic discoveries using human intestinal organoids and human enteric viral pathogens.

Air-Liquid-Interface Differentiated Human Nose Epithelium: A Robust Primary Tissue Culture Model of SARS-CoV-2 Infection

“…Alarmingly, toxicity in humans can be fatal as was seen with an HBV antiviral (fialuridine, FIAU) due to toxicity to a human mitochondrial gene, which was not seen in pre-clinical animal models, including non-human primates [ 40 , 41 ]. The promise of human tissue stem cell-derived organoids is to fill the gap between animal and cell line pre-clinical models and humans [ 3 , 4 , 5 , 8 ]. Organoids recapitulate key features of human tissue in a dish and thus offer physiologically relevant models of host–virus interaction.…”

“…Human adult stem cell-derived organoids fill the gap between animal and cell line pre-clinical models, and human clinical trials. Tissue stem cells ‘remember’ their tissue of origin, they generate the same cell types in a dish as they do in the body and recapitulate key features of architecture and function of the parent tissue [ 3 , 4 , 5 , 6 , 7 , 8 ]. Early studies by the Clevers [ 9 ] and Estes [ 10 ] laboratories exemplified the power of tissue stem cell derived organoids for modelling lung (respiratory syncytial virus (RSV)) and gut (human noroviruses (HuNoVs)) infection, respectively.…”

Rotavirus-Induced Lipid Droplet Biogenesis Is Critical for Virus Replication

“…These nontransformed, multicellular, physiologically active, and organotypic cultures recapitulate the relevant heterogenous cell types that comprise the intestinal villus epithelium. Recent studies using HIEs are revealing previously unknown host-microbe interactions that affect pathogen replication and outcomes of human infections ( Crawford et al, 2021 ). Infection of HIEs with human RVs have demonstrated host range and cell type restriction, and virus-induced fluid secretion ( Saxena et al, 2016 ).…”

Advances in understanding of the innate immune response to human norovirus infection using organoid models

“…HIEs and organoid cultures [40, 44–47] have created platforms to study the cellular processes and signalling pathways involved in restricting replication of enteric viruses including human norovirus [48, 49]. Human intestinal organoids (HIO) and HIE are three-dimensional (3D) cultures containing multiple intestinal cell types that are derived from Lgr5+ intestinal stem cells [44] ().…”