A robust human norovirus replication model in zebrafish larvae.

Jana Van Dycke,Peter De Witte,Joana Rocha-Pereira,Johan Neyts,Jan Maes,Nádia Conceição-Neto,Tatiane C Nogueira,Arno Cuvry,Ian Goodfellow,Myra Hosmillo,Annelii Ny,Erik Verbeken,Jelle Matthijnssens,Mehul Suthar

doi:10.1371/journal.ppat.1008009

Jana Van Dycke, Peter De Witte + Show 12 more

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https://doi.org/10.1371/journal.ppat.1008009

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Abstract

Human noroviruses (HuNoVs) are the most common cause of foodborne illness, with a societal cost of $60 billion and 219,000 deaths/year. The lack of robust small animal models has significantly hindered the understanding of norovirus biology and the development of effective therapeutics. Here we report that HuNoV GI and GII replicate to high titers in zebrafish (Danio rerio) larvae; replication peaks at day 2 post infection and is detectable for at least 6 days. The virus (HuNoV GII.4) could be passaged from larva to larva two consecutive times. HuNoV is detected in cells of the hematopoietic lineage and the intestine, supporting the notion of a dual tropism. Antiviral treatment reduces HuNoV replication by >2 log10, showing that this model is suited for antiviral studies. Zebrafish larvae constitute a simple and robust replication model that will largely facilitate studies of HuNoV biology and the development of antiviral strategies.

Highlights

Human noroviruses (HuNoVs) are an important cause of epidemic and sporadic acute gastroenteritis worldwide; annually about 700 million people develop a human norovirus (HuNoV) infection resulting in ~219,000 deaths and a societal cost estimated at 60 billion US dollars [1]
Outbreaks of acute HuNoV gastroenteritis occur often, but chronic infections happen in people with immune deficiencies
Despite its clinical relevance, studying the virus has been a decades-long challenge because no simple and efficient cultivation system existed. This has recently started to change; we here contribute with an important step forward by establishing an in vivo model system to study HuNoV replication using zebrafish larvae

Summary

Introduction

Human noroviruses (HuNoVs) are an important cause of epidemic and sporadic acute gastroenteritis worldwide; annually about 700 million people develop a HuNoV infection resulting in ~219,000 deaths and a societal cost estimated at 60 billion US dollars [1]. Knowledge on the biology and pathogenesis of human noroviruses largely depends upon the development of robust and physiologically relevant cultivation systems. HuNoV replication has been reported in large animals such as chimpanzees, gnotobiotic pigs and calves. There is an urgent need for simpler, more robust, widely available HuNoV replication models. Such models should contribute to a better understanding of the biology of HuNoV replication and infection, this will significantly facilitate larger-scale research efforts, such as the development of therapeutic strategies

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