tetano
Editor, Senior Moderator
Published ahead of print 4 June 2014, doi: 10.1128/JVI.00676-14 JVI.00676-14
Host Species Restriction of Middle East Respiratory Syndrome Coronavirus through its Receptor Dipeptidyl Peptidase 4
Neeltje van Doremalen1,
Kerri L. Miazgowicz1,
Shauna Milne-Price1,
Trenton Bushmaker1,
Shelly Robertson1,
Dana Scott2,
Joerg Kinne3,
Jason S. McLellan4,
Jiang Zhu5 and
Vincent J. Munster1#
1Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
2Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
3Central Veterinary Research Laboratories, Dubai, P.O. Box 597, Dubai, UAE
4Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
5Department of Immunology and Microbial Science, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
ABSTRACT
Middle East Respiratory Syndrome coronavirus (MERS-CoV) emerged in 2012. Recently the MERS-CoV receptor dipeptidyl peptidase 4 (DPP4) was identified and the specific interaction of the receptor-binding domain (RBD) of MERS-CoV spike protein and DPP4 was determined by crystallography. Animal studies identified rhesus macaques but not hamsters, ferrets or mice to be susceptible for MERS-CoV. Here we investigated the role of DPP4 in this observed species tropism. Cell lines of human and non-human primate origin were permissive of MERS-CoV, whereas hamster, ferret or mouse cell lines were not, despite presence of DPP4. Expression of human DPP4 in non-susceptible BHK and ferret cells enabled MERS-CoV replication, whereas expression of hamster or ferret DPP4 did not. Modeling the binding energies of MERS-CoV spike protein RBD to DPP4 of human (susceptible) or hamster (non-susceptible) identified five amino acid residues involved in the DPP4-RBD interaction. Expression of hamster DPP4 containing the five human DPP4 amino acids rendered BHK cells susceptible to MERS-CoV, whereas expression of human DPP4 containing the five hamster DPP4 amino acids did not. Using the same approach, the potential of MERS-CoV to utilize the DPP4s of common Middle Eastern livestock was investigated. Modeling of the DPP4 MERS-CoV RBD interaction predicted the ability of MERS-CoV to bind the DPP4s of camel, goat, cow and sheep. Expression of the DPP4s of these species on BHK cells supported MERS-CoV replication. This suggests, together with the abundant DPP4 presence in the respiratory tract, that these species might be able to function as a MERS-CoV intermediate reservoir.
Importance The ongoing outbreak of Middle East Respiratory Syndrome coronavirus (MERS-CoV) has caused 184 laboratory confirmed cases to date, with 80 fatalities. Although bats and dromedary camels have been identified as potential MERS-CoV hosts, the virus has so far not been isolated from any species other than humans. The inability of MERS-CoV to infect commonly used animal models such as hamster, mice and ferrets, indicates the presence of a species barrier. We show that the MERS-CoV receptor DPP4 plays a pivotal role in the observed species tropism of MERS-CoV and subsequently identified the amino acids in DPP4 responsible for this restriction. Using a combined modeling and experimental approach we predict that based on the ability of MERS-CoV to utilize the DPP4 of common Middle East livestock species, such as camels, goats, sheep and cows, these form a potential MERS-CoV intermediate host reservoir species.
http://jvi.asm.org/content/early/2014/05/28/JVI.00676-14.abstract
Host Species Restriction of Middle East Respiratory Syndrome Coronavirus through its Receptor Dipeptidyl Peptidase 4
Neeltje van Doremalen1,
Kerri L. Miazgowicz1,
Shauna Milne-Price1,
Trenton Bushmaker1,
Shelly Robertson1,
Dana Scott2,
Joerg Kinne3,
Jason S. McLellan4,
Jiang Zhu5 and
Vincent J. Munster1#
1Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
2Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
3Central Veterinary Research Laboratories, Dubai, P.O. Box 597, Dubai, UAE
4Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
5Department of Immunology and Microbial Science, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
ABSTRACT
Middle East Respiratory Syndrome coronavirus (MERS-CoV) emerged in 2012. Recently the MERS-CoV receptor dipeptidyl peptidase 4 (DPP4) was identified and the specific interaction of the receptor-binding domain (RBD) of MERS-CoV spike protein and DPP4 was determined by crystallography. Animal studies identified rhesus macaques but not hamsters, ferrets or mice to be susceptible for MERS-CoV. Here we investigated the role of DPP4 in this observed species tropism. Cell lines of human and non-human primate origin were permissive of MERS-CoV, whereas hamster, ferret or mouse cell lines were not, despite presence of DPP4. Expression of human DPP4 in non-susceptible BHK and ferret cells enabled MERS-CoV replication, whereas expression of hamster or ferret DPP4 did not. Modeling the binding energies of MERS-CoV spike protein RBD to DPP4 of human (susceptible) or hamster (non-susceptible) identified five amino acid residues involved in the DPP4-RBD interaction. Expression of hamster DPP4 containing the five human DPP4 amino acids rendered BHK cells susceptible to MERS-CoV, whereas expression of human DPP4 containing the five hamster DPP4 amino acids did not. Using the same approach, the potential of MERS-CoV to utilize the DPP4s of common Middle Eastern livestock was investigated. Modeling of the DPP4 MERS-CoV RBD interaction predicted the ability of MERS-CoV to bind the DPP4s of camel, goat, cow and sheep. Expression of the DPP4s of these species on BHK cells supported MERS-CoV replication. This suggests, together with the abundant DPP4 presence in the respiratory tract, that these species might be able to function as a MERS-CoV intermediate reservoir.
Importance The ongoing outbreak of Middle East Respiratory Syndrome coronavirus (MERS-CoV) has caused 184 laboratory confirmed cases to date, with 80 fatalities. Although bats and dromedary camels have been identified as potential MERS-CoV hosts, the virus has so far not been isolated from any species other than humans. The inability of MERS-CoV to infect commonly used animal models such as hamster, mice and ferrets, indicates the presence of a species barrier. We show that the MERS-CoV receptor DPP4 plays a pivotal role in the observed species tropism of MERS-CoV and subsequently identified the amino acids in DPP4 responsible for this restriction. Using a combined modeling and experimental approach we predict that based on the ability of MERS-CoV to utilize the DPP4 of common Middle East livestock species, such as camels, goats, sheep and cows, these form a potential MERS-CoV intermediate host reservoir species.
http://jvi.asm.org/content/early/2014/05/28/JVI.00676-14.abstract