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Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus.
Cold Spring Harb Mol Case Stud. 2016 11; 2(6):a001214.CS

Abstract

Genome sequence analysis of Middle East respiratory syndrome coronavirus (MERS-CoV) variants from patient specimens has revealed the evolutionary dynamics and mechanisms of pathogenesis of the virus. However, most studies have analyzed the consensus sequences of MERS-CoVs, precluding an investigation of intrapatient heterogeneity. Here, we analyzed non-consensus sequences to characterize intrapatient heterogeneity in cases associated with the 2015 outbreak of MERS in South Korea. Deep-sequencing analysis of MERS-CoV genomes performed on specimens from eight patients revealed significant intrapatient variation; therefore, sequence heterogeneity was further analyzed using targeted deep sequencing. A total of 35 specimens from 24 patients (including a super-spreader) were sequenced to detect and analyze variants displaying intrapatient heterogeneity. Based on the analysis of non-consensus sequences, we demonstrated the intrapatient heterogeneity of MERS-CoVs, with the highest level in the super-spreader specimen. The heterogeneity could be transmitted in a close association with variation in the consensus sequences, suggesting the occurrence of multiple MERS-CoV infections. Analysis of intrapatient heterogeneity revealed a relationship between D510G and I529T mutations in the receptor-binding domain (RBD) of the viral spike glycoprotein. These two mutations have been reported to reduce the affinity of the RBD for human CD26. Notably, although the frequency of both D510G and I529T varied greatly among specimens, the combined frequency of the single mutants was consistently high (87.7% ± 1.9% on average). Concurrently, the frequency of occurrence of the wild type at the two positions was only 6.5% ± 1.7% on average, supporting the hypothesis that selection pressure exerted by the host immune response played a critical role in shaping genetic variants and their interaction in human MERS-CoVs during the outbreak.

Authors+Show Affiliations

Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea.Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea.Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Company Limited, Seoul 06351, South Korea.Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea.Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, South Korea.Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, South Korea.Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.Samsung Genome Institute, Samsung Medical Center, Seoul 06351, South Korea;; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27900364

Citation

Park, Donghyun, et al. "Analysis of Intrapatient Heterogeneity Uncovers the Microevolution of Middle East Respiratory Syndrome Coronavirus." Cold Spring Harbor Molecular Case Studies, vol. 2, no. 6, 2016, pp. a001214.
Park D, Huh HJ, Kim YJ, et al. Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus. Cold Spring Harb Mol Case Stud. 2016;2(6):a001214.
Park, D., Huh, H. J., Kim, Y. J., Son, D. S., Jeon, H. J., Im, E. H., Kim, J. W., Lee, N. Y., Kang, E. S., Kang, C. I., Chung, D. R., Ahn, J. H., Peck, K. R., Choi, S. S., Kim, Y. J., Ki, C. S., & Park, W. Y. (2016). Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus. Cold Spring Harbor Molecular Case Studies, 2(6), a001214.
Park D, et al. Analysis of Intrapatient Heterogeneity Uncovers the Microevolution of Middle East Respiratory Syndrome Coronavirus. Cold Spring Harb Mol Case Stud. 2016;2(6):a001214. PubMed PMID: 27900364.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus. AU - Park,Donghyun, AU - Huh,Hee Jae, AU - Kim,Yeon Jeong, AU - Son,Dae-Soon, AU - Jeon,Hyo-Jeong, AU - Im,Eu-Hyun, AU - Kim,Jong-Won, AU - Lee,Nam Yong, AU - Kang,Eun-Suk, AU - Kang,Cheol In, AU - Chung,Doo Ryeon, AU - Ahn,Jin-Hyun, AU - Peck,Kyong Ran, AU - Choi,Sun Shim, AU - Kim,Yae-Jean, AU - Ki,Chang-Seok, AU - Park,Woong-Yang, PY - 2016/12/1/entrez PY - 2016/12/3/pubmed PY - 2017/11/29/medline KW - recurrent upper and lower respiratory tract infections SP - a001214 EP - a001214 JF - Cold Spring Harbor molecular case studies JO - Cold Spring Harb Mol Case Stud VL - 2 IS - 6 N2 - Genome sequence analysis of Middle East respiratory syndrome coronavirus (MERS-CoV) variants from patient specimens has revealed the evolutionary dynamics and mechanisms of pathogenesis of the virus. However, most studies have analyzed the consensus sequences of MERS-CoVs, precluding an investigation of intrapatient heterogeneity. Here, we analyzed non-consensus sequences to characterize intrapatient heterogeneity in cases associated with the 2015 outbreak of MERS in South Korea. Deep-sequencing analysis of MERS-CoV genomes performed on specimens from eight patients revealed significant intrapatient variation; therefore, sequence heterogeneity was further analyzed using targeted deep sequencing. A total of 35 specimens from 24 patients (including a super-spreader) were sequenced to detect and analyze variants displaying intrapatient heterogeneity. Based on the analysis of non-consensus sequences, we demonstrated the intrapatient heterogeneity of MERS-CoVs, with the highest level in the super-spreader specimen. The heterogeneity could be transmitted in a close association with variation in the consensus sequences, suggesting the occurrence of multiple MERS-CoV infections. Analysis of intrapatient heterogeneity revealed a relationship between D510G and I529T mutations in the receptor-binding domain (RBD) of the viral spike glycoprotein. These two mutations have been reported to reduce the affinity of the RBD for human CD26. Notably, although the frequency of both D510G and I529T varied greatly among specimens, the combined frequency of the single mutants was consistently high (87.7% ± 1.9% on average). Concurrently, the frequency of occurrence of the wild type at the two positions was only 6.5% ± 1.7% on average, supporting the hypothesis that selection pressure exerted by the host immune response played a critical role in shaping genetic variants and their interaction in human MERS-CoVs during the outbreak. SN - 2373-2873 UR - https://www.unboundmedicine.com/medline/citation/27900364/Analysis_of_intrapatient_heterogeneity_uncovers_the_microevolution_of_Middle_East_respiratory_syndrome_coronavirus_ L2 - http://molecularcasestudies.cshlp.org/cgi/pmidlookup?view=long&pmid=27900364 DB - PRIME DP - Unbound Medicine ER -