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Ca2+ Ions Promote Fusion of Middle East Respiratory Syndrome Coronavirus with Host Cells and Increase Infectivity.
Straus, Marco R; Tang, Tiffany; Lai, Alex L; Flegel, Annkatrin; Bidon, Miya; Freed, Jack H; Daniel, Susan; Whittaker, Gary R.
  • Straus MR; Department of Microbiology and Immunology, Cornell University, Ithaca, New York, USA.
  • Tang T; Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, USA.
  • Lai AL; ACERT, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
  • Flegel A; Department of Microbiology and Immunology, Cornell University, Ithaca, New York, USA.
  • Bidon M; Institute of Veterinary Biochemistry, Freie Universität Berlin, Berlin, Germany.
  • Freed JH; Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, USA.
  • Daniel S; ACERT, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA.
  • Whittaker GR; Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, USA sd386@cornell.edu grw7@cornell.edu.
J Virol ; 94(13)2020 06 16.
Article in English | MEDLINE | ID: covidwho-1583223
Semantic information from SemMedBD (by NLM)
1. Host Cell PART_OF Middle East Respiratory Syndrome Coronavirus
Subject
Host Cell
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PART_OF
Object
Middle East Respiratory Syndrome Coronavirus
2. FES wt Allele|FDPS|FES PART_OF Middle East Respiratory Syndrome Coronavirus
Subject
FES wt Allele|FDPS|FES
Predicate
PART_OF
Object
Middle East Respiratory Syndrome Coronavirus
3. calcium ion PART_OF Protoplasm
Subject
calcium ion
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PART_OF
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Protoplasm
4. Communicable Disease PROCESS_OF C0008139
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Communicable Disease
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C0008139
5. Communicable Disease PROCESS_OF C0013127
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Communicable Disease
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C0013127
6. Confirmed case PROCESS_OF Homo sapiens
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Confirmed case
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Homo sapiens
7. Host Cell PART_OF Middle East Respiratory Syndrome Coronavirus
Subject
Host Cell
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PART_OF
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Middle East Respiratory Syndrome Coronavirus
8. FES wt Allele|FDPS|FES PART_OF Middle East Respiratory Syndrome Coronavirus
Subject
FES wt Allele|FDPS|FES
Predicate
PART_OF
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Middle East Respiratory Syndrome Coronavirus
9. calcium ion PART_OF Protoplasm
Subject
calcium ion
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PART_OF
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Protoplasm
10. Communicable Diseases, Emerging PROCESS_OF Chiroptera
Subject
Communicable Diseases, Emerging
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Chiroptera
11. Communicable Diseases, Emerging PROCESS_OF Camelus dromedarius
Subject
Communicable Diseases, Emerging
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PROCESS_OF
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Camelus dromedarius
12. Confirmed case PROCESS_OF Homo sapiens
Subject
Confirmed case
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Homo sapiens
ABSTRACT
Fusion with, and subsequent entry into, the host cell is one of the critical steps in the life cycle of enveloped viruses. For Middle East respiratory syndrome coronavirus (MERS-CoV), the spike (S) protein is the main determinant of viral entry. Proteolytic cleavage of the S protein exposes its fusion peptide (FP), which initiates the process of membrane fusion. Previous studies on the related severe acute respiratory syndrome coronavirus (SARS-CoV) FP have shown that calcium ions (Ca2+) play an important role in fusogenic activity via a Ca2+ binding pocket with conserved glutamic acid (E) and aspartic acid (D) residues. SARS-CoV and MERS-CoV FPs share a high sequence homology, and here, we investigated whether Ca2+ is required for MERS-CoV fusion by screening a mutant array in which E and D residues in the MERS-CoV FP were substituted with neutrally charged alanines (A). Upon verifying mutant cell surface expression and proteolytic cleavage, we tested their ability to mediate pseudoparticle (PP) infection of host cells in modulating Ca2+ environments. Our results demonstrate that intracellular Ca2+ enhances MERS-CoV wild-type (WT) PP infection by approximately 2-fold and that E891 is a crucial residue for Ca2+ interaction. Subsequent electron spin resonance (ESR) experiments revealed that this enhancement could be attributed to Ca2+ increasing MERS-CoV FP fusion-relevant membrane ordering. Intriguingly, isothermal calorimetry showed an approximate 11 MERS-CoV FP to Ca2+ ratio, as opposed to an 12 SARS-CoV FP to Ca2+ ratio, suggesting significant differences in FP Ca2+ interactions of MERS-CoV and SARS-CoV FP despite their high sequence similarity.IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) is a major emerging infectious disease with zoonotic potential and has reservoirs in dromedary camels and bats. Since its first outbreak in 2012, the virus has repeatedly transmitted from camels to humans, with 2,468 confirmed cases causing 851 deaths. To date, there are no efficacious drugs and vaccines against MERS-CoV, increasing its potential to cause a public health emergency. In order to develop novel drugs and vaccines, it is important to understand the molecular mechanisms that enable the virus to infect host cells. Our data have found that calcium is an important regulator of viral fusion by interacting with negatively charged residues in the MERS-CoV FP region. This information can guide therapeutic solutions to block this calcium interaction and also repurpose already approved drugs for this use for a fast response to MERS-CoV outbreaks.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Calcium / Coronavirus Infections / Virus Internalization / Host-Pathogen Interactions / Middle East Respiratory Syndrome Coronavirus / Ions / Membrane Fusion Type of study: Prognostic study Topics: Vaccines Limits: Animals / Humans Language: English Year: 2020 Document Type: Article Affiliation country: JVI.00426-20

Full text: Available Collection: International databases Database: MEDLINE Main subject: Calcium / Coronavirus Infections / Virus Internalization / Host-Pathogen Interactions / Middle East Respiratory Syndrome Coronavirus / Ions / Membrane Fusion Type of study: Prognostic study Topics: Vaccines Limits: Animals / Humans Language: English Year: 2020 Document Type: Article Affiliation country: JVI.00426-20