OmniVira

Literature detail

Adaptive Evolution of MERS-CoV to Species Variation in DPP4.

Michael Letko1 Kerri Miazgowicz2,3 Rebekah McMinn2,4 Stephanie N Seifert5 Isabel Sola6 Luis Enjuanes6 Aaron Carmody7 Neeltje van Doremalen5 Vincent Munster8
Affiliations 8 institutions
  1. Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA. Electronic address: [email protected].
  2. Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
  3. Department of Infectious Diseases, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA.
  4. Department of Microbiology, Immunology, & Pathology, Colorado State University, Fort Collins, CO 80523, USA.
  5. Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
  6. Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Campus Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
  7. Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
  8. Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA. Electronic address: [email protected].
PMID 30110630 2018 Cell Rep eng ppublish
PubMed DOI Browse context

Article

Publication summary

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) likely originated in bats and passed to humans through dromedary camels; however, the genetic mechanisms underlying cross-species adaptation remain poorly understood. Variation in the host receptor, dipeptidyl peptidase 4 (DPP4), can block the interaction with the MERS-CoV spike protein and form a species barrier to infection. To better understand the species adaptability of MERS-CoV, we identified a suboptimal species-derived variant of DPP4 to study viral adaption. Passaging virus on cells expressing this DPP4 variant led to accumulation of mutations in the viral spike which increased replication. Parallel passages revealed distinct paths of viral adaptation to the same DPP4 variant. Structural analysis and functional assays showed that these mutations enhanced viral entry with suboptimal DPP4 by altering the surface charge of spike. These findings demonstrate that MERS-CoV spike can utilize multiple paths to rapidly adapt to novel species variation in DPP4.

Adaptation Bat Coronavirus Desmodus rotundus Dipeptidyl peptidase IV DPP4 Evolution MERS Species barrier Spike Zoonosis Biological Coevolution Adaptation, Physiological Amino Acid Sequence Animals Binding Sites Chiroptera Chlorocebus aethiops

Structured evidence records

Evidence records

4 total
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.90
Key finding

MERS-CoV accumulated distinct spike mutations during passage on cells expressing a suboptimal species-derived DPP4 variant, revealing multiple evolutionary pathways for adaptation to variation in host receptor DPP4.

Virus
MERS-CoV
Location
Not specified
Supporting text

Passaging virus on cells expressing this DPP4 variant led to accumulation of mutations in the viral spike which increased replication. Parallel passages revealed distinct paths of viral adaptation to the same DPP4 variant.

Genes or proteins
spike
Analysis methods
experimental passaging; mutation analysis; structural analysis
Host Range Experiment 1 records
Host Range Experiment Extraction confidence 0.85
Key finding

MERS-CoV adapted during in vitro passage on cells carrying a species-derived DPP4 variant, acquiring spike mutations that increased replication and entry efficiency with non-optimal receptors.

Virus
MERS-CoV
Location
Not specified
Supporting text

Passaging virus on cells expressing this DPP4 variant led to accumulation of mutations in the viral spike which increased replication. Structural analysis and functional assays showed that these mutations enhanced viral entry with suboptimal DPP4.

Method
passage experiment; functional assay; replication assay
Experimental system
in vitro cell culture
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 1.00
Key finding

MERS-CoV acquired spike mutations that enhanced replication and entry by adapting to a suboptimal species variant of the DPP4 receptor.

Virus
MERS-CoV
Host
Not specified
Location
Not specified
Supporting text

Passaging virus on cells expressing this DPP4 variant led to accumulation of mutations in the viral spike which increased replication. Structural analysis and functional assays showed that these mutations enhanced viral entry with suboptimal DPP4 by altering the surface charge of spike.

Genes or proteins
spike; DPP4
Receptors
DPP4
Mechanism types
receptor_binding; cell_entry; replication_efficiency; host_factor_interaction
Receptor Usage 1 records
Receptor Usage Extraction confidence 0.95
Key finding

MERS-CoV spike protein mutations enhanced viral entry and replication with suboptimal DPP4 receptor variants, demonstrating receptor-mediated adaptation to species variation.

Virus
MERS-CoV
Location
Not specified
Supporting text

Variation in the host receptor, dipeptidyl peptidase 4 (DPP4), can block the interaction with the MERS-CoV spike protein and form a species barrier to infection. Passaging virus on cells expressing this DPP4 variant led to accumulation of mutations in the viral spike which increased replication. Structural analysis and functional assays showed that these mutations enhanced viral entry with suboptimal DPP4 by altering the surface charge of spike.

Method
passaging; structural analysis; functional assays
Receptors
DPP4