title: Spread of Mutant Middle East Respiratory Syndrome Coronavirus with Reduced Affinity to Human CD26 during the South Korean Outbreak.
abstract: The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe respiratory infection with a high mortality rate (~35%). MERS-CoV has been a global threat due to continuous outbreaks in the Arabian peninsula and international spread by infected travelers since 2012. From May to July 2015, a large outbreak initiated by an infected traveler from the Arabian peninsula swept South Korea and resulted in 186 confirmed cases with 38 deaths (case fatality rate, 20.4%). Here, we show the rapid emergence and spread of a mutant MERS-CoV with reduced affinity to the human CD26 receptor during the South Korean outbreak. We isolated 13 new viral genomes from 14 infected patients treated at a hospital and found that 12 of these genomes possess a point mutation in the receptor-binding domain (RBD) of viral spike (S) protein. Specifically, 11 of these genomes have an I529T mutation in RBD, and 1 has a D510G mutation. Strikingly, both mutations result in reduced affinity of RBD to human CD26 compared to wild-type RBD, as measured by surface plasmon resonance analysis and cellular binding assay. Additionally, pseudotyped virus bearing an I529T mutation in S protein showed reduced entry into host cells compared to virus with wild-type S protein. These unexpected findings suggest that MERS-CoV adaptation during human-to-human spread may be driven by host immunological pressure such as neutralizing antibodies, resulting in reduced affinity to host receptor, and thereby impairs viral fitness and virulence, rather than positive selection for a better affinity to CD26.
  
  
  OBJECTIVE
  Recently, a large outbreak initiated by an MERS-CoV-infected traveler from the Middle East swept South Korea and resulted in 186 confirmed cases with 38 deaths. This is the largest outbreak outside the Middle East, and it raised strong concerns about the possible emergence of MERS-CoV mutations. Here, we isolated 13 new viral genomes and found that 12 of them possess a point mutation in the receptor-binding domain of viral spike protein, resulting in reduced affinity to the human cognate receptor, CD26, compared to the wild-type virus. These unexpected findings suggest that MERS-CoV adaptation in humans may be driven by host immunological pressure.
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors.forename: Shinhye
authors.initials: S
authors.lastname: Cheon
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Chan-Ki
authors.initials: CK
authors.lastname: Min
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors.forename: Kyung Mok
authors.initials: KM
authors.lastname: Sohn
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Ying Jin
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Young-Je
authors.initials: YJ
authors.lastname: Cha
authors.affiliation: Institute of Biotechnology, Cosmogenetech Inc., Seoul, Republic of Korea.
authors.forename: Ju-Il
authors.initials: JI
authors.lastname: Kang
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Seong Kyu
authors.initials: SK
authors.lastname: Han
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Ha
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Gwanghun
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Abdimadiyeva
authors.initials: A
authors.lastname: Aigerim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea Institute of Endemic Disease, Seoul National University Medical Research Center and Bundang Hospital, Seoul, Republic of Korea.
authors.forename: Hyun Mu
authors.initials: HM
authors.lastname: Shin
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea Institute of Endemic Disease, Seoul National University Medical Research Center and Bundang Hospital, Seoul, Republic of Korea.
authors.forename: Myung-Sik
authors.initials: MS
authors.lastname: Choi
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Sanguk
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea idalicekim@gmail.com chonh@snu.ac.kr.
authors.forename: Yeon-Sook
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea Institute of Endemic Disease, Seoul National University Medical Research Center and Bundang Hospital, Seoul, Republic of Korea idalicekim@gmail.com chonh@snu.ac.kr.
authors.forename: Nam-Hyuk
authors.initials: NH
authors.lastname: Cho
mesh_terms: D000220:Adaptation, Biological; D018352:Coronavirus Infections / Q000453:epidemiology* / Q000821:virology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004196:Disease Outbreaks; D016679:Genome, Viral; D006801:Humans; D065207:Middle East Respiratory Syndrome Coronavirus / Q000302:isolation & purification / Q000502:physiology*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D017354:Point Mutation; D011485:Protein Binding; D011991:Receptors, Virus / Q000378:metabolism*; D056910:Republic of Korea / Q000453:epidemiology; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D064370:Spike Glycoprotein, Coronavirus / Q000235:genetics / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D053585:Virus Attachment
chemical_list: D050505:Mutant Proteins; D011991:Receptors, Virus; D064370:Spike Glycoprotein, Coronavirus; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4