Bile acids and ceramide overcome the entry restriction for GII.3 human norovirus replication in human intestinal enteroids.

Autor:	Murakami K; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.; Department of Virology II, National Institute of Infectious Diseases, Musashi-murayama, Tokyo 208-0011, Japan., Tenge VR; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Karandikar UC; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Lin SC; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Ramani S; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Ettayebi K; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Crawford SE; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Zeng XL; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Neill FH; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Ayyar BV; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030., Katayama K; Department of Virology II, National Institute of Infectious Diseases, Musashi-murayama, Tokyo 208-0011, Japan.; Laboratory of Viral Infection I, Kitasato Institute for Life Sciences, Kitasato University, Tokyo 108-8641, Japan., Graham DY; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.; Department of Medicine, Michael E. DeBakey VA Medical Center, Houston, TX 77030.; Department of Medicine, Baylor College of Medicine, Houston, TX 77030., Bieberich E; Department of Physiology, University of Kentucky, Lexington, KY 40506., Atmar RL; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.; Department of Medicine, Baylor College of Medicine, Houston, TX 77030., Estes MK; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030; mestes@bcm.edu.; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jan 21; Vol. 117 (3), pp. 1700-1710. Date of Electronic Publication: 2020 Jan 02.
DOI:	10.1073/pnas.1910138117
Abstrakt:	Human noroviruses (HuNoVs) cause sporadic and epidemic outbreaks of gastroenteritis in all age groups worldwide. We previously reported that stem cell-derived human intestinal enteroid (HIE) cultures support replication of multiple HuNoV strains and that some strains (e.g., GII.3) replicate only in the presence of bile. Heat- and trypsin-treatment of bile did not reduce GII.3 replication, indicating a nonproteinaceous component in bile functions as an active factor. Here we show that bile acids (BAs) are critical for GII.3 replication and replication correlates with BA hydrophobicity. Using the highly effective BA, glycochenodeoxycholic acid (GCDCA), we show BAs act during the early stage of infection, BA-dependent replication in HIEs is not mediated by detergent effects or classic farnesoid X receptor or Takeda G protein-coupled receptor 5 signaling but involves another G protein-coupled receptor, sphingosine-1-phosphate receptor 2, and BA treatment of HIEs increases particle uptake. We also demonstrate that GCDCA induces multiple cellular responses that promote GII.3 replication in HIEs, including enhancement of 1) endosomal uptake, 2) endosomal acidification and subsequent activity of endosomal/lysosomal enzyme acid sphingomyelinase (ASM), and 3) ceramide levels on the apical membrane. Inhibitors of endosomal acidification or ASM reduce GII.3 infection and exogenous addition of ceramide alone permits infection. Furthermore, inhibition of lysosomal exocytosis of ASM, which is required for ceramide production at the apical surface, decreases GII.3 infection. Together, our results support a model where GII.3 exploits rapid BA-mediated cellular endolysosomal dynamic changes and cellular ceramide to enter and replicate in jejunal HIEs. Competing Interests: Competing interest statement: M.K.E. is named as an inventor on patents related to cloning and cultivation of the Norwalk virus genome and is a consultant to and received research funding from Takeda Vaccines, Inc. R.L.A. has received research funding from Takeda Vaccines, Inc.
Databáze:	MEDLINE
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