A second open reading frame in human enterovirus determines viral replication in intestinal epithelial cells

• Published in: Nature communications Vol. 10; no. 1; pp. 4066 - 9
• Main Authors: Guo, Haoran, Li, Yan, Liu, Guanchen, Jiang, Yunhe, Shen, Siyu, Bi, Ran, Huang, Honglan, Cheng, Tong, Wang, Chunxi, Wei, Wei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.09.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 14/19; 14/34; 14/63; 45/77; 631/326/596/2555; 631/45/612/1256; 64/60; 82/80; Amino Acid Sequence; Base Sequence; Disruption; Ectopic expression; Enterovirus - genetics; Enterovirus - physiology; Enterovirus Infections - transmission; Enterovirus Infections - virology; Enteroviruses; Epithelial cells; Epithelial Cells - virology; Feces - virology; Host-Pathogen Interactions - genetics; HT29 Cells; Humanities and Social Sciences; Humans; Infections; Intestine; Intestines - cytology; Intestines - virology; multidisciplinary; Open reading frames; Open Reading Frames - genetics; Polyproteins; Proteins; Replication; RNA viruses; RNA Viruses - genetics; RNA Viruses - physiology; Science; Science (multidisciplinary); Viral Proteins - genetics; Viral Proteins - metabolism; Virus Replication - genetics; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12040-9

Human enteroviruses (HEVs) of the family Picornaviridae , which comprises non-enveloped RNA viruses, are ubiquitous worldwide. The majority of EV proteins are derived from viral polyproteins encoded by a single open reading frame (ORF). Here, we characterize a second ORF in HEVs that is crucial for viral intestinal infection. Disruption of ORF2p expression decreases the replication capacity of EV-A71 in human intestinal epithelial cells (IECs). Ectopic expression of ORF2p proteins derived from diverse enteric enteroviruses sensitizes intestinal cells to the replication of ORF2p-defective EV-A71 and respiratory enterovirus EV-D68. We show that the highly conserved WIGHPV domain of ORF2p is important for ORF2p-dependent viral intestinal infection. ORF2p expression is required for EV-A71 particle release from IECs and can support productive EV-D68 infection in IECs by facilitating virus release. Our results indicate that ORF2p is a determining factor for enteric enterovirus replication in IECs. The majority of enterovirus proteins are encoded as polyprotein in one open reading frame. Here, Guo et al . characterize a second open reading frame in human enteroviruses and show that it is important for viral particle release, particularly in epithelial cells, and that it affects mortality in a mouse model.