Journal article
Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism
Proceedings of the National Academy of Sciences, USA, Vol.113(43), pp.12262-12262
10/01/2016
DOI: 10.1073/pnas.1608147113
PMCID: PMC5086990
PMID: 27791014
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) infects humans from zoonotic sources and causes severe pulmonary disease. Virions require spike (S) glycoproteins for binding to cell receptors and for catalyzing virus-cell membrane fusion. Fusion occurs only after S proteins are cleaved sequentially, first during their secretion through the exocytic organelles of virus-producing cells, and second after virus binding to target-cell receptors. To more precisely determine how sequential proteolysis contributes to CoV infection, we introduced S mutations obstructing the first cleavages. These mutations severely compromised MERS-CoV infection into human lung-derived cells, but had little effect on infection into several other cell types. These cell type-specific requirements for proteolysis correlated with S conformations during cell entry. Without the first cleavages, S proteins resisted cell receptor-induced conformational changes, which restricted the second, fusion-activating cleavages. Consistent with these findings, precleaved MERS viruses used receptor-proximal, cell-surface proteases to effect the second fusion-activating cleavages during cell entry, whereas the more rigid uncleaved MERS viruses trafficked past these cell-surface proteases and into endosomes. Uncleaved viruses were less infectious to human airway epithelial and Calu3 cell cultures because they lacked sufficient endosomal fusion-activating proteases. Thus, by sensitizing viruses to receptor-induced conformational changes, the first S cleavages expand virus tropism to cell types that are relevant to lung infection, and therefore may be significant determinants of MERS-CoV virulence.
Details
- Title: Subtitle
- Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism
- Creators
- Jung-Eun ParkKun Li - University of Iowa, Stead Family Department of PediatricsArlene BarlanAnthony R FehrStanley Perlman - University of Iowa, Microbiology and ImmunologyPaul B McCray Jr - University of Iowa, Stead Family Department of PediatricsTom Gallagher
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences, USA, Vol.113(43), pp.12262-12262
- DOI
- 10.1073/pnas.1608147113
- PMID
- 27791014
- PMCID
- PMC5086990
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: P01 AI 060699
- Language
- English
- Date published
- 10/01/2016
- Academic Unit
- Microbiology and Immunology; Pulmonary Medicine; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
- Record Identifier
- 9983777471702771
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