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

Abstract

Norovirus is the leading cause of epidemic and endemic acute gastroenteritis worldwide and the most frequent cause of foodborne illness in the United States. There is no specific treatment for norovirus infections and therapeutic interventions are based on alleviating symptoms and limiting viral transmission. The immune response to norovirus is not completely understood and mechanistic studies have been hindered by lack of a robust cell culture system. In recent years, the human intestinal enteroid/human intestinal organoid system (HIE/HIO) has enabled successful human norovirus replication. Cells derived from HIE have also successfully been subjected to genetic manipulation using viral vectors as well as CRISPR/Cas9 technology, thereby allowing studies to identify antiviral signaling pathways important in controlling norovirus infection. RNA sequencing using HIE cells has been used to investigate the transcriptional landscape during norovirus infection and to identify antiviral genes important in infection. Other cell culture platforms such as the microfluidics-based gut-on-chip technology in combination with the HIE/HIO system also have the potential to address fundamental questions on innate immunity to human norovirus. In this review, we highlight the recent advances in understanding the innate immune response to human norovirus infections in the HIE system, including the application of advanced molecular technologies that have become available in recent years such as the CRISPR/Cas9 and RNA sequencing, as well as the potential application of single cell transcriptomics, viral proteomics, and gut-on-a-chip technology to further elucidate innate immunity to norovirus.

State-of-the-art analytical methods of viral infections in human lung organoids

“…The SARS-CoV-2 exposure of most animal models either did not lead to infection, or only partly reflect relevant human aspects of disease [2][3][4]. Hence, human-based organ models provide promising opportunities for the rapid study of pathogens and their impact on the human system [5][6][7][8][9][10]. To investigate the effects of a viral pathogen on our respiratory system, human alveolar-like organoids serve as an excellent tool to gain insights on virulence mechanisms and viral tropisms [11].…”

Material Engineering in Gut Microbiome and Human Health

“…After deriving the gut organoids, host-gut microbiome interactions can be studied by colonizing the organoids with microbiota consortia. For example, human norovirus, which causes nearly 700 million cases of gastroenteritis annually, could not be cultivated in previous epithelial cell cultures or small animal models yet can be successfully grown in an intestinal organoid model with robust replications in vitro [ 162 , 166 ]. Key characteristics of norovirus were also recapitulated in the organoid culture in a host-specific manner.…”

“…Key characteristics of norovirus were also recapitulated in the organoid culture in a host-specific manner. For instance, organoids derived from individuals lacking genes encoding functional fucosyltransferase 2 enzymes showed reduced susceptibility to norovirus replication [ 166 ]. Such new understanding of host-specific pathogenesis obtained from gut organoid-microbiome cocultures thus have enormous potential for screening antiviral drugs.…”

Low-Cost, Real-Time Polymerase Chain Reaction System for Point-of-Care Medical Diagnosis

“…Drinking water wells used in many parts of the world are also a major source of bacterial contamination [ 2 , 3 , 4 ]. Norovirus is a leading cause of epidemic and endemic acute gastroenteritis worldwide, affecting children particularly [ 5 , 6 ]. These situations show the need for low-cost, real-time and rapid bacterial testing in food and drinking water.…”