Molecular epidemiology and evolutionary histories of human coronavirus OC43 and HKU1 among patients with upper respiratory tract infections in Kuala Lumpur, Malaysia

Virology Journal, Feb 2016

Background Despite the worldwide circulation of human coronavirus OC43 (HCoV-OC43) and HKU1 (HCoV-HKU1), data on their molecular epidemiology and evolutionary dynamics in the tropical Southeast Asia region is lacking. Methods The study aimed to investigate the genetic diversity, temporal distribution, population history and clinical symptoms of betacoronavirus infections in Kuala Lumpur, Malaysia between 2012 and 2013. A total of 2,060 adults presented with acute respiratory symptoms were screened for the presence of betacoronaviruses using multiplex PCR. The spike glycoprotein, nucleocapsid and 1a genes were sequenced for phylogenetic reconstruction and Bayesian coalescent inference. Results A total of 48/2060 (2.4 %) specimens were tested positive for HCoV-OC43 (1.3 %) and HCoV-HKU1 (1.1 %). Both HCoV-OC43 and HCoV-HKU1 were co-circulating throughout the year, with the lowest detection rates reported in the October-January period. Phylogenetic analysis of the spike gene showed that the majority of HCoV-OC43 isolates were grouped into two previously undefined genotypes, provisionally assigned as novel lineage 1 and novel lineage 2. Sign of natural recombination was observed in these potentially novel lineages. Location mapping showed that the novel lineage 1 is currently circulating in Malaysia, Thailand, Japan and China, while novel lineage 2 can be found in Malaysia and China. Molecular dating showed the origin of HCoV-OC43 around late 1950s, before it diverged into genotypes A (1960s), B (1990s), and other genotypes (2000s). Phylogenetic analysis revealed that 27.3 % of the HCoV-HKU1 strains belong to genotype A while 72.7 % belongs to genotype B. The tree root of HCoV-HKU1 was similar to that of HCoV-OC43, with the tMRCA of genotypes A and B estimated around the 1990s and 2000s, respectively. Correlation of HCoV-OC43 and HCoV-HKU1 with the severity of respiratory symptoms was not observed. Conclusions The present study reported the molecular complexity and evolutionary dynamics of human betacoronaviruses among adults with acute respiratory symptoms in a tropical country. Two novel HCoV-OC43 genetic lineages were identified, warranting further investigation on their genotypic and phenotypic characteristics.

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Molecular epidemiology and evolutionary histories of human coronavirus OC43 and HKU1 among patients with upper respiratory tract infections in Kuala Lumpur, Malaysia

Al-Khannaq et al. Virology Journal Molecular epidemiology and evolutionary histories of human coronavirus OC43 and HKU1 among patients with upper respiratory tract infections in Kuala Lumpur, Malaysia Maryam Nabiel Al-Khannaq 3 Kim Tien Ng 3 Xiang Yong Oong 3 Yong Kek Pang 3 Yutaka Takebe 1 2 3 Jack Bee Chook 3 Nik Sherina Hanafi 4 Adeeba Kamarulzaman 3 Kok Keng Tee 0 0 Department of Medical Microbiology, Faculty of Medicine, University of Malaya , Kuala Lumpur , Malaysia 1 School of Medicine, Yokohama City University , Yokohama, Kanagawa , Japan 2 AIDS Research Center, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo , Japan 3 Department of Medicine, Faculty of Medicine, University of Malaya , Kuala Lumpur , Malaysia 4 Department of Primary Care Medicine, Faculty of Medicine, University of Malaya , Kuala Lumpur , Malaysia Background: Despite the worldwide circulation of human coronavirus OC43 (HCoV-OC43) and HKU1 (HCoV-HKU1), data on their molecular epidemiology and evolutionary dynamics in the tropical Southeast Asia region is lacking. Methods: The study aimed to investigate the genetic diversity, temporal distribution, population history and clinical symptoms of betacoronavirus infections in Kuala Lumpur, Malaysia between 2012 and 2013. A total of 2,060 adults presented with acute respiratory symptoms were screened for the presence of betacoronaviruses using multiplex PCR. The spike glycoprotein, nucleocapsid and 1a genes were sequenced for phylogenetic reconstruction and Bayesian coalescent inference. Results: A total of 48/2060 (2.4 %) specimens were tested positive for HCoV-OC43 (1.3 %) and HCoV-HKU1 (1.1 %). Both HCoV-OC43 and HCoV-HKU1 were co-circulating throughout the year, with the lowest detection rates reported in the October-January period. Phylogenetic analysis of the spike gene showed that the majority of HCoV-OC43 isolates were grouped into two previously undefined genotypes, provisionally assigned as novel lineage 1 and novel lineage 2. Sign of natural recombination was observed in these potentially novel lineages. Location mapping showed that the novel lineage 1 is currently circulating in Malaysia, Thailand, Japan and China, while novel lineage 2 can be found in Malaysia and China. Molecular dating showed the origin of HCoV-OC43 around late 1950s, before it diverged into genotypes A (1960s), B (1990s), and other genotypes (2000s). Phylogenetic analysis revealed that 27.3 % of the HCoV-HKU1 strains belong to genotype A while 72.7 % belongs to genotype B. The tree root of HCoV-HKU1 was similar to that of HCoV-OC43, with the tMRCA of genotypes A and B estimated around the 1990s and 2000s, respectively. Correlation of HCoV-OC43 and HCoV-HKU1 with the severity of respiratory symptoms was not observed. Conclusions: The present study reported the molecular complexity and evolutionary dynamics of human betacoronaviruses among adults with acute respiratory symptoms in a tropical country. Two novel HCoV-OC43 genetic lineages were identified, warranting further investigation on their genotypic and phenotypic characteristics. Coronaviruses; Molecular epidemiology; Phylogenetics; Upper respiratory infection; Virus evolution Background Human coronaviruses are common cold viruses that are frequently found to be associated with acute upper respiratory tract infections (URTIs) [ 1 ]. According to the International Committee for Taxonomy of Viruses (ICTV), human coronavirus OC43 (HCoV-OC43) and HKU1 (HCoV-HKU1) belong to the betacoronavirus genus, a member of the Coronaviridae family. Coronaviruses contain the largest RNA genomes and have been established as one of the rapidly evolving viruses [ 2 ]. In addition to the high nucleotide substitution rates across the genome [ 3 ], the coronavirus genome is subjected to homologous recombination during viral replication, which is caused by RNA template switching mediated by the copy-choice mechanism [ 4, 5 ]. The genetic recombination of coronaviruses had possibly led to the emergence of lethal pathogens such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), which caused up to 50 % mortality in infected individuals [ 6–9 ]. Recombination events in the spike (S), nucleocapsid (N) and the RNA dependent RNA polymerase (RdRp) within the 1a gene of HCoV-OC43 and HCoV-HKU1 leading to the emergence of unique recombinant genotypes have been reported [ 10, 11 ]. Studies have shown that HCoV-OC43 is often associated with approximately 5 % of acute respiratory infections while the more recent HCoV-HKU1 is less prevalent [ 12, 13 ]. In humans, acute upper respiratory symptoms such as nasal congestion and rhinorrhea are relatively common in HCoV infections while sore throat and hoarseness of voice are less common, with cough usually associated with HCoV-OC43 infection [14]. In tropical countries, annual shift in the predominant genotype has been documented, with (...truncated)


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Maryam Al-Khannaq, Kim Ng, Xiang Oong, Yong Pang, Yutaka Takebe, Jack Chook, Nik Hanafi, Adeeba Kamarulzaman, Kok Tee. Molecular epidemiology and evolutionary histories of human coronavirus OC43 and HKU1 among patients with upper respiratory tract infections in Kuala Lumpur, Malaysia, Virology Journal, 2016, pp. 33, 13, DOI: 10.1186/s12985-016-0488-4