OmniVira

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].
PMID30110630 DOI10.1016/j.celrep.2018.07.045 Year2018 Journal Cell reports Cell Rep Languageeng Statusppublish

Abstract

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.

Supporting text Virus Host Location
Adaptation 13 Bat 54 Coronavirus 195 Desmodus rotundus 4 Dipeptidyl peptidase IV 1 DPP4 3 Evolution 62 MERS 4 Species barrier 2 Spike 25 Zoonosis 116 Biological Coevolution 2 Adaptation, Physiological 33 Amino Acid Sequence 128 Animals 1948 Binding Sites 89 Chiroptera 371 Chlorocebus aethiops 70 Cricetulus 7 Dipeptidyl Peptidase 4 32 Gene Expression 10 Host Specificity 132 Host-Pathogen Interactions 55 Humans 1440

Evidence records

2 total
Experimental Infection
1 records · 1 evidence types
Evidence type Host Range Experiment
1 records
OVE3071 Host Range Experiment
Key finding

Passaging MERS-CoV on cells expressing a species-derived DPP4 variant led to adaptive spike mutations that increased viral replication.

Virus
Middle East Respiratory Syndrome Coronavirus
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. These findings demonstrate that MERS-CoV spike can utilize multiple paths to rapidly adapt to novel species variation in DPP4.

Method
virus passaging | cell culture infection assay | replication measurement
Experimental system
cell culture system expressing species-derived DPP4 receptor variant
Genomic Evolution
1 records · 1 evidence types
Evidence type Phylogenetic Evolution
1 records
OVE3074 Phylogenetic Evolution
Key finding

Parallel passages of MERS-CoV on cells expressing the same suboptimal DPP4 variant led to distinct evolutionary routes of spike adaptation, showing multiple paths for species-specific receptor adaptation.

Virus
Middle East Respiratory Syndrome Coronavirus
Host
Not specified
Location
Not specified
Supporting text

Parallel passages revealed distinct paths of viral adaptation to the same DPP4 variant. These findings demonstrate that MERS-CoV spike can utilize multiple paths to rapidly adapt to novel species variation in DPP4.

Genes or proteins
spike
Analysis methods
experimental evolution | comparative genomic analysis