When a Stomach Bug Comes Calling

Abstract

They say that an army marches on its stomach, and while history provides ample illustration of the value of robust supply lines, the quality of the stores being delivered matters equally. In our modern world (where a growing population is truly an army writ large), food safety is of paramount importance for human health and economic stability. Viral and bacterial gastrointestinal infections transmitted from individual to individual during food preparation or from compromised food sources directly can be acutely debilitating and even fatal for subsets of the population, including young children. Recent insights into how microbes like norovirus and Vibrio parahaemolyticus interact with host cells and the resulting implications for vaccines or treatments will be welcomed by anyone hoping for a gastroenteritis-free cruise, seafood dinner, or quick takeout lunch. Although valiant volunteers have contributed to human studies of norovirus infection, it is vital to have model systems that recapitulate key features of human pathogenesis if there are to be systematic investigations of the host-pathogen interactions. Norovirus is a leading cause of food-borne gastroenteritis (Kirk et al., 2016Kirk M.D. Pires S.M. Black R.E. Caipo M. Crump J.A. Devleesschauwer B. Dopfer D. Fazil A. Fischer-Walker C.L. Hald T. et al.PLoS Med. 2016; 12: e1001921Crossref Scopus (781) Google Scholar), but it’s not been possible to examine infection by human-tropic strains in a tractable culture system. New work using human intestinal enteroids (Ettayebi et al., 2016Ettayebi K. Crawford S.E. Murakami K. Broughman J.R. Karandikar U. Tnege V.R. Neill F.H. Blutt S.E. Zeng X.-L. Qu L. et al.Science. 2016; (Published online August 25, 2016)https://doi.org/10.1126/science.aaf5211Crossref PubMed Scopus (843) Google Scholar) changes that. Organoids generated from human intestinal stem cells support infection and replication of several human noroviruses. The system reproduces aspects of human infection patterns, including exclusive infection of enterocytes and modulation of infectivity based on histone blood group antigens. Intriguingly, the authors found that a non-proteinaceous host factor, present in bile, abets human norovirus infection. This culture system paves the way for the directed studies of norovirus biology and host interactions that are essential for development of vaccines and antiviral treatments, which are entirely lacking (Prasad et al., 2016Prasad B.V. Shanker S. Muhaxhiri Z. Deng L. Choi J.M. Estes M.K. Song Y. Palzkill T. Atmar R.L. Curr. Opin. Vir. 2016; 18: 117-125Crossref PubMed Scopus (35) Google Scholar). With the culture system in hand, where to start the next line of inquiries is a major question. A big hint comes from recent work by the Virgin lab (Orchard et al., 2016Orchard R.C. Wilen C.B. Doench J.G. Baldrige M.T. McCune B.T. Lee Y.C. Lee S. Pruett-Miller S.M. Nelson C.A. Fremont D.H. et al.Science. 2016; 353: 933-936Crossref PubMed Scopus (176) Google Scholar) that identifies a candidate host receptor for murine norovirus. A cell-based CRISPR-Cas screen for host factors contributing to infection of mouse microglial cells by a murine norovirus revealed a cell-surface protein previously associated with myeloid cell activation as a major receptor for the virus. Loss of the protein, CD300lf, blocks viral entry into cells and prevents infection in mouse models. Perhaps most strikingly, expression of the mouse protein in human cells enabled cross-species infection, which is not otherwise observed. Similar to the case with human enteroids, a non-proteinaceous co-factor contributes to the interaction between CD300lf and the murine virus. Whether these two groups are looking at related entities remains to be seen. The identification of a single protein as the key murine norovirus receptor stands in contrast to previous basic and epidemiological studies of the human norovirus family that point to surface glycans and an individual’s expression of a specific fucosyltransferase (FUT2) playing a substantial role in host susceptibility (Kambhampati et al., 2015Kambhampati A. Payne D.C. Cosantini V. Lopman B.A. Clin. Infect. Dis. 2015; 62: 11-18Crossref PubMed Scopus (80) Google Scholar). If a similar dependency on a protein receptor bears out for human-tropic viruses, this finding may spur new branch-off points for antiviral development (Prasad et al., 2016Prasad B.V. Shanker S. Muhaxhiri Z. Deng L. Choi J.M. Estes M.K. Song Y. Palzkill T. Atmar R.L. Curr. Opin. Vir. 2016; 18: 117-125Crossref PubMed Scopus (35) Google Scholar). Which is not to say that carbohydrates can be dismissed as mediators of pathogenesis. Norovirus is only one pathogen impinging on food safety. For Vibrio parahaemolyticus, a bacterium that causes gastroenteritis from contaminated seafood, glycans matter. V. parahaemolyticus uses two different type III secretion systems (T3SS 1 and 2) to introduce cell death effectors into host cells. A CRISPR-Cas screen looking for impediments to killing human intestinal epithelial cells identified distinct carbohydrate maturation pathways as essential for operation of T3SS1 and T3SS2 independently (Blondel et al., 2016Blondel C.J. Park J.S. Hubbard T.P. Pacheco A.R. Kuehl C.J. Walsh M.J. Davis B.M. Gewurz B.E. Doench J.G. Waldor M.K. Cell Host Microbe. 2016; 20: 226-237Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Terminal fucosylation of cell surface proteins proved sufficient for T3SS2, a major agent for intestinal colonization, to achieve effector protein delivery. In this case, it doesn’t come down to carbohydrate modification of a specific protein. Rather, it seems that the surface landscape is integral for association and effective access of the pathogen effectors. Once among the most common pathogens causing enteric distress, particularly in children, rotavirus is now being controlled by vaccination. Yet an analysis by the World Health Organization recently identified more than 20 other microbes that significantly impact food safety (Kirk et al., 2016Kirk M.D. Pires S.M. Black R.E. Caipo M. Crump J.A. Devleesschauwer B. Dopfer D. Fazil A. Fischer-Walker C.L. Hald T. et al.PLoS Med. 2016; 12: e1001921Crossref Scopus (781) Google Scholar). We’re a long way from being able to treat them all. We’ve all had colleagues (or have been the unlucky one ourselves) who’ve missed out on work or play because of a stomach bug. With the development of a means to study human norovirus and new insights into how related viruses and a pathogenic bacterium beat down the door to a host cell, the situation and promise for development of effective treatments looks brighter.