Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism Journal Article

Authors: Park, J. E.; Li, K.; Barlan, A.; Fehr, A. R.; Perlman, S.; McCray, P. B., Jr; Gallagher, T.
Article Title: Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism
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.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 113
Issue: 43
ISSN: 1091-6490; 0027-8424
Publisher: Unknown  
Journal Place: United States
Date Published: 2016
Start Page: 12262
End Page: 12267
Language: eng
Notes: LR: 20170425; GR: P01 AI060699/AI/NIAID NIH HHS/United States; GR: P01 HL051670/HL/NHLBI NIH HHS/United States; GR: P01 HL091842/HL/NHLBI NIH HHS/United States; GR: P30 DK054759/DK/NIDDK NIH HHS/United States; JID: 7505876; OTO: NOTNLM; ppublish