Enterovirus 71 infection of human airway organoids reveals VP1-145 as a viral infectivity determinant

Abstract

Human enteroviruses frequently cause severe diseases in children. Human enteroviruses are transmitted via the fecal–oral route and respiratory droplets, and primary replication occurs in the gastro-intestinal and respiratory tracts; however, how enteroviruses infect these sites is largely unknown. Human intestinal organoids have recently proven to be valuable tools for studying enterovirus–host interactions in the intestinal tract. In this study, we demonstrated the susceptibility of a newly developed human airway organoid model for enterovirus 71 (EV71) infection. We showed for the first time in a human physiological model that EV71 replication kinetics are strain-dependent. A glutamine at position 145 of the VP1 capsid protein was identified as a key determinant of infectivity, and residues VP1-98K and VP1-104D were identified as potential infectivity markers. The results from this study provide new insights into EV71 infectivity in the human airway epithelia and demonstrate the value of organoid technology for virus research.

These authors contributed equally: Sabine M.G. van der Sanden, is currently working at Arthrogen BV, 1105 BA Amsterdam, The Netherlands, Norman Sachs

These authors contributed equally: Sabine M.G. van der Sanden, is currently working at Arthrogen BV, 1105 BA Amsterdam, The Netherlands, Norman Sachs

Acknowledgements

The B3 SK-EV006 and B4 C7-Osaka strains and infectious cDNA clones of strains C1 02363 and C2 1095 were kindly provided by Dr. H. Shimizu and Dr. Y. Nishimura (National Institute of Infectious Diseases, Japan). Strains C4 75-Yamagata and C5 209-VN were kindly provided by Dr. K. Mizuta (Yamagata Prefectural Institute of Public Health, Japan) and Dr. Thao and Dr. Tu (Pasteur Institute, Ho Chi Minh City, Vietnam), respectively. EV71 C1 strains 7765, 1416, and 1185 were provided by Dr. E. Duizer and Dr. K. Benschop (National Institute for Public Health and the Environment, the Netherlands). The infectious clone of B3 SK-EV006 was provided by Professor Dr. P. McMinn (University of Sydney, Australia). This work was supported by the European Union’s Seventh Framework Marie-Curie IAPP AIROPico (http://www.airopico.eu) REA-grant-agreement, no. 612308.

Conflict of interest

N.S. and H.C. are inventors on patents/patent applications related to organoid technology. The other authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Information accompanies this paper at (10.1038/s41426-018-0077-2).