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The Origins of G12P[6] Rotavirus Strains Detected in Lebanon

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The Origins of G12P[6] Rotavirus Strains Detected in Lebanon RESEARCH ARTICLE Reslan et al., Journal of General Virology DOI 10.1099/jgv.0.001535 The origins of G12P[6] rotavirus strains detected in Lebanon Lina Reslan1,2†, Nischay Mishra3†, Marc Finianos1, Kimberley Zakka1, Amanda Azakir1,4, Cheng Guo3, Riddhi Thakka3, Ghassan Dbaibo1,2, W. Ian Lipkin3,* and Hassan Zaraket1,4,* Abstract The G12 rotaviruses are an increasingly important cause of severe diarrhoea in infants and young children worldwide. Seven human G12P[6] rotavirus strains were detected in stool samples from children hospitalized with gastroenteritis in Lebanon during a 2011–2013 surveillance study. Complete genomes of these strains were sequenced using VirCapSeq- VERT, a capture- based high- throughput viral- sequencing method, and further characterized based on phylogenetic analyses with global RVA and vaccine strains. Based on the complete genomic analysis, all Lebanese G12 strains were found to have Wa- like genetic backbone G12- P[6]-I1- R1- C1- M1- A1- N1- T1- E1- H1. Phylogenetically, these strains fell into two clusters where one of them might have emerged from Southeast Asian strains and the second one seems to have a mixed backbone between North Ameri- can and Southeast Asian strains. Further analysis of these strains revealed high antigenic variability compared to available vaccine strains. To our knowledge, this is the first report on the complete genome- based characterization of G12P[6] emerging in Lebanon. Additional studies will provide important insights into the evolutionary dynamics of G12 rotaviruses spreading in Asia. INTRODUCTION (glycoprotein), are found on the double-shelled capsid Group A rotavirus (RVA) infection is the global leading structure, and are used as determinants of serotype specificity cause of severe, dehydrating diarrhoea in children younger [3]. Currently, more than 60 G/P combinations have been than 5 years. Although the pathogenic burden of rotavirus identified in human infections globally with the following has decreased during the past decade, rotaviruses were genotypes accounting for the majority of the strains: G1, G2, nonetheless responsible for nearly 130 000 deaths annu- G3, G4, G9 and G12, in association with P[4], P[6], P [8] ally [1]. In Lebanon, RVA accounts for nearly one third of [4]. RVA’s segmented RNA genome and error- prone RNA- gastroenteritis- associated hospitalizations in children under dependent RNA polymerase contribute to its high diversity 5 years of age [2]. through reassortment, recombination and mutations. Reas- sortment between human and animal viruses reveal that RVA is a non-enveloped double- stranded RNA virus of the animal- to- human transmission contributes to the increased Reoviridae family. Its genome is composed of 11 segments, RVA diversity [5–7]. coding for six structural viral proteins (VPs) and six non- structural proteins (NSPs). Each segment codes for one G12 strains have been increasingly detected globally, viral protein, except for segment 11, that codes for two becoming the sixth major human G genotype [8, 9]. They proteins (NSP5 and NSP6). Two of the viral proteins, VP4 have emerged predominantly in combination with either P[6] (non- glycosylated protease- sensitive protein) and VP7 or P[8], and less commonly with P[4] or P[9] genotype. In Received 21 August 2020; Accepted 18 November 2020; Published 17 December 2020 Author affiliations: 1Center for Infectious Diseases Research, American University of Beirut, Faculty of Medicine, Beirut, Lebanon; 2Department of Pediatrics and Adolescent Medicine, American University of Beirut, Faculty of Medicine, Beirut, Lebanon; 3Center for Infection and the Immunity, Mailman School of Public Health, Columbia University, NY 10032, New York; 4Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, Beirut, Lebanon. *Correspondence: Hassan Zaraket, hz34@ aub. edu. lb; W. Ian Lipkin, wil2001@ cumc. columbia. edu Keywords: Human Rotavirus A; G12P[6]; Genome; Lebanon; VirCapSeq- VERT. Abbreviations: MENA, Middle East and North Africa; NSPs, non-structural proteins; RVA, Group A rotavirus; USA, United States of America; VPs, viral proteins. The nucleotide sequences of the full- length genome of G12P[6] strains of this study were deposited in GenBank under accession numbers: M13 (MN746056- MN746066); M21 (MN746067- MN746077); M23 (MN746078- MN746088); R99 (MN746089- MN746099), R80 (MN746100- MN746110); H280 (MN746045- MN746055); and H270 (MN746034- MN746034). †These authors contributed equally to this work One supplementary table is available with the online version of this article. 001535 © 2020 The Authors 1 Reslan et al., Journal of General Virology 2020 Table 1. Demographic and clinical characteristics of patients with G12P[6] Vomiting Diarrhoea Severity of dehydration Patient Specimen collection Age (m/d)* Gender Temperature Episodes/day Duration Episodes/day Duration (%) Vesikari ID date (mm/yy)* (°C) (days) (days) score M13 02/2011 12 d Male 38 3 1 3 4 1–5 % 11 M21 03/2011 12 m Male 39 5 3 4 3 1–5 % 18 M23 03/2011 6 m Female 39 5 2 3 7 1–5 % 17 R99 04/2013 31 m Male 38.5 8 3 4 2 1–5 % 15 R80 06/2012 11 m Female 39.5 4 3 4 5 1–5 % 17 H280 02/2013 8 m Male 38.5 4 2 6 1 1–5 % 14 H270 01/2013 35 m Male 40 3 4 5 7 1–5 % 17 *m, month; y, year; *d, day. the Middle East and North Africa (MENA), G12 strains have gastroenteritis was assessed using the previously described been reported in several countries; Saudi Arabia [10], Yemen 20- point Vesikari scoring system manual [22]. [11], Iraq [12], Iran [13], Tunisia [14, 15], Egypt [16], Pakistan [17] and Turkey [18]. Whole-genome sequencing An extended classification and nomenclature system was VirCapSeq- VERT library preparation and sequencing were implemented by the Rotavirus Classification Working Group, performed as previously described [23]. Total nucleic acid to define genotypes of each genome segment. The notation was extracted from stool suspension using the NucliSENS Gx- P[x]-Ix- Rx- Cx- Mx- Ax- Nx- Tx- Ex- Hx (‘x’ representing easyMAG automated platform (BioMérieux, Boxtel, The the genotype number) denotes the VP7- VP4- VP6- VP1- VP2- Netherlands) followed by cDNA synthesis. The libraries VP3- NSP1- NSP2- NSP3- NSP4- NSP5 genes, respectively. To were prepared using the Hyper Prep kit (KAPA Biosystems, date, at least 35 G, 50 P, 26 I, 21 R, 19 C, 19 M, 30 A, 20 N, Boston, MA, USA) and unique barcodes and hybridized 21T, 26E and 21 H genotypes have been described (http:// with the VirCapSeq-VERT probe set prior to a final PCR rega. kuleuven. be/ cev/ viralmetagenomics/ virus- classifica- and sequencing (Illumina HiSeq 4000). The obtained reads tion). Worldwide, the majority of human RVA strains possess were then trimmed to remove low-quality sequences and were either genotype 1, constellation Wa- like (I1- R1- C1- M1- A1- assembled using Geneious 11.0.2. Individual gene segments N1- T1- E1- H1), or the genotype 2, constellation DS-1- like were then genotyped using the Virus Pathogen Database (I2- R2- C2- M2- A2- N2- T2- E2- H2) [19]. However, strains of and Analysis Resource (VIPR) (https://www. viprbrc. org/ mixed Wa- like/DS-1- like constellations have also emerged brc/ rvaGenotyper. spg? method= ShowCleanInputPage& [20]. decorator= reo). In the present study, we attempted to investigate the genomic diversity and origin of G12P[6] RVA strains that we previ- Phylogenetic analyses ously identified in Lebanon during a prospective, multicenter, Phylogenetic analysis was performed using the maximum- hospital- based surveillance study conducted between 2011 likelihood method after selecting the best- fit evolutionary and 2013 [21]. model for the data set, based on the value of the lowest corrected Akaike information criterion (AICc) using mega 6.06 software [24]. Models used in this study were Tamura METHODS 3- parameter (T92)+G+I (NSP1, NSP2, VP1, VP3, VP7), Sample selection T92+G (VP6, NSP3, NSP4, NSP5/6), Tamura- Nei parameter (TN93)+G (VP2), TN93+G+I (VP4). Statistical analyses were The seven G12P[6] RVA- positive samples included in this performed using bootstrap method with 1000 replicates. study were identified during a surveillance study that was conducted in Lebanon during years 2011 through 2013 to The nucleotide sequences of the full- length genome of G12P[6] determine the incidence of RVA- associated gastroenteritis in strains of this study were deposited in GenBank under hospitalized children under 5 years of age [21]. The G12P[6] accession numbers: M13 (MN746056- MN746066); M21 strains are M21, M13, M23, H280, H270, R80 and R99. (MN746067- MN746077); M23 (MN746078- MN746088); R99 The demographic and clinical features of the patients were (MN746089- MN746099), R80 (MN746100- MN746110); H280 obtained along with the specimens. The severity of RVA (MN746045- MN746055); and H270 (MN746034- MN746034). 2 Reslan et al., Journal of General Virology 2020 Prediction of glycosylation sites H270, R80 and R99 clustered closely with G12P[6] strains The N- linked glycosylation sites (N- X- S or T patterns, where from Thailand and Korea. X can be any amino acid other than proline) were predicted The VP1, VP2, VP3 and VP6 gene sequences of strains M21, using the NetNGlyc 1.0 server (http://www. cbs. dtu. dk/ M13 and M23 had the highest nucleotide sequence identities services/ NetNGlyc/). with either Myanmar G12P[6] strain A23 (99.4%–99.5 %) or Nepali G12P[6] strain 10N4594 (99.4%–99.7 %). Phylogeneti- RESULTS cally, VP1, VP2, VP3 and VP6 of these strains clustered with G12P[6] strains from Nepal and Myanmar. The VP6 gene Clinical features of detected Lebanese G12P[6] clustered additionally with two USA strains VU12-13-103 strains and VU12-13-76. The demographic distribution and clinical characteristics of H270, H280, R80 and R99 possessed VP1 genes sharing the children detected with G12P[6] strains are displayed in highest similarity to G1P[8] strains CK00084 from Australia Table 1. In total, seven G12P[6] specimens (out of 428 RVA- (99.4%–99.9 %), 2008747323 from the USA (99.3%–99.4 %) positive stool specimens) were collected from hospitalized and clustered together with G1P[8] and G12P[8] from children with severe gastroenteritis: M13, M21 and M23 were Australia, Italy, Malawi and other countries.
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