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Molecular Characterization of VP4 and NSP4 Genes from Rotavirus Strains Infecting Neonates and Young Children in Belem,´ Brazil Joana D’Arc P

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Molecular Characterization of VP4 and NSP4 Genes from Rotavirus Strains Infecting Neonates and Young Children in Belem,´ Brazil Joana D’Arc P Virus Research 126 (2007) 149–158 Molecular characterization of VP4 and NSP4 genes from rotavirus strains infecting neonates and young children in Belem,´ Brazil Joana D’Arc P. Mascarenhas a,∗, Alexandre C. Linhares a, Yvone B. Gabbay a, Clarissa S. Lima a, Sylvia de Fatima´ S. Guerra a, Luana S. Soares a, Darleise S. Oliveira a, Jackson C. Lima b, Olinda Macedoˆ a, Jose´ Paulo G. Leite c a Se¸c˜ao de Virologia, Instituto Evandro Chagas, Secretaria de Vigilˆancia em Sa´ude, Minist´erio da Sa´ude, Rodovia BR 316 KM 07, S/N, Levilˆandia, 67.030-000 Ananindeua, Par´a, Brazil b Departamento de Inform´atica em Sa´ude, Universidade Federal de S˜ao Paulo, S˜ao Paulo, Brazil c Departamento de Virologia, Instituto Oswaldo Cruz, Funda¸c˜ao Oswaldo Cruz, Rio de Janeiro, Brazil Received 10 November 2006; received in revised form 8 February 2007; accepted 10 February 2007 Available online 21 March 2007 Abstract Several reports have identified P[6] specificities in humans and in animals in different countries of the world, but few sequence data are available in public databases. In this work we have characterized the VP4 strains bearing P[6] specificity and NSP4 genotypes among diarrheic young children and diarrheic and non-diarrheic neonates from three studies previously conducted in Belem,´ Northern region of Brazil. As the to VP8* fragment, we observed a close relationship to both human prototypes of lineage P[6]-Ia (bootstrap of 99%) and porcine sublineages Ib and Ic (89.2–98.1% aa similarity and mean of 95%). With regards to the NSP4, the samples clustered into genotypes A and B. Of note, of the 27 P[6] strains analyzed in the present study and classified as genotype B, 8 (29.6%) were more similar to porcine prototypes when VP8* and NSP4 genes are compared, and were recovered, one from a neonate and seven from diarrheic children. These preliminary findings reinforce that further investigations are needed to assess the relative frequencies of P[6] strains in our region, as well as to investigate the potential for interspecies transmission involving humans and animals, particularly pigs. © 2007 Elsevier B.V. All rights reserved. Keywords: P[6] genotype; Neonates; Diarrheic children; Interspecies transmission 1. Introduction segments of double-stranded RNA (dsRNA), which encodes six structural (VP1–VP4, VP6 and VP7) and six non-structural Worldwide, group A human rotaviruses (HRV) are important (NSP1–NSP6) proteins (Estes, 2001; Kapikian et al., 2001). Pro- cause of severe gastroenteritis among infants and young chil- teolytic cleavage of VP4 generates two smaller polypeptides dren, as well as in young animals of a wide variety of species designated VP5* and VP8*. Antigenic analyses have demon- (Kapikian et al., 2001). The Rotavirus comprises a single genus strated that the VP8* subunit possesses the major epitopes within the Reoviridae family with a genome consisting of 11 responsible for serotype specificity (Estes and Cohen, 1989). Human group A comprises at least 27 P and 15 G genotypes cod- ing by VP4 and VP7 genes, respectively (Estes, 2001; Kapikian ∗ Corresponding author. Tel.: +55 91 32142016; fax: +55 91 32142006. et al., 2001; Khamrin et al., 2007; Martella et al., 2006b; Rahman E-mail addresses: [email protected] (J.D.P. Mascarenhas), [email protected] (A.C. Linhares), et al., 2005; Rao et al., 2000; Steyer et al., 2007). [email protected] (Y.B. Gabbay), The rotavirus non-structural protein NSP4, encoded by gene [email protected] (C.S. Lima), segment 10, has 175 amino acids (aa) in length. NSP4, specifi- [email protected] (S.d.F.S. Guerra), cally 22 aa corresponding to residues 114–135, appears to induce [email protected] (L.S. Soares), diarrhea in young mice and may be a key determinant of rotavirus [email protected] (D.S. Oliveira), NSP4 [email protected] (J.C. Lima), pathogenicity (Ball et al., 1996; Tian et al., 1995). The [email protected] (O. Macedo),ˆ gene has been classified into groups A, B and C. Group A com- jpgleite@ioc.fiocruz.br (J.P.G. Leite). prises five genotypes: A (KUN), B (Wa), C (AU-1), D (EW) and 0168-1702/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.virusres.2007.02.010 150 J.D.P. Mascarenhas et al. / Virus Research 126 (2007) 149–158 E (avian-like) (Ciarlet et al., 2000; Ito et al., 2001; Mori et al., al., 2001, 2002; Banyai´ et al., 2004; Fang et al., 2002; Laird et al., 2002). 2003; Leite et al., 1996; Mascarenhas et al., 2002, 2006, 2007; Rotavirus strains bearing P[6] genotype represent one of the Page and Steele, 2004; Salu et al., 2003; Santos et al., 1994; three most common VP4 specificities associated with human Steele and Ivanoff, 2003; Steele and Sears, 1996; Timenetsky et infections (Santos and Hoshino, 2005). Originally, the M37 al., 1994; Volotao˜ et al., 2006). and RV3 prototypes with P[6] serotype have been associated Although several reports have documented P[6] specificity with avirulent neonatal strains recovered from asymptomatic and it has been identified in humans and animals in different neonates (Flores et al., 1986; Hoshino et al., 1985), and was countries of the world, few sequence data are available in public the basis for developing candidate vaccines (Barnes et al., 1997, databases (Banyai´ et al., 2004). These studies have been sup- 2002; Flores et al., 1990; Midthun et al., 1991; Vesikari et al., ported by phylogenetic analysis and suggest that interspecies 1991). transmission may occur (Martella et al., 2006a; Rahman et al., Worldwide, P[6] genotype strains have been recovered from 2003). diarrheic and non-diarrheic neonates (Cunliffe et al., 2002; In this study we analyzed VP4 and NSP4 genes from Linhares et al., 2002; Pager et al., 2000; Steele et al., 1992, 27 P[6] rotavirus strains obtained from diarrheic and non- 1995) and young children (Adah et al., 1997, 2001; Araujo´ et diarrheic neonates and diarrheic young children during 1990 Fig. 1. Characteristics of VP4 P[6] rotavirus isolates from three surveys conducted in Belem,´ Brazil. Study A, Surveillance for young children participating in a trial with a reassortant tetravalent vaccine against rotavirus (RRV-TV) conducted from 1990 to 1992 (Linhares et al., 1996; Mascarenhas et al., 2002); Study B, surveillance for rotavirus infection in a neonatal care unit wards at a public hospital in Belem,´ Brazil, conducted from 1996 to 1998 (Linhares et al., 2002; Mascarenhas et al., 2006, 2007); Study C, surveillance for hospitalized diarrheic young children and those attending an outpatient heath unit conducted from May 1998 to May 2000 (Gabbay et al., 2002; Mascarenhas et al., 2003). J.D.P. Mascarenhas et al. / Virus Research 126 (2007) 149–158 151 and 2000, from studies previously conducted in Belem,´ Northern Prism 3100 automatic sequencer (Applied Biosystems, Foster Brazil. City, CA, USA). The sequences obtained for the VP4 and the NSP4 genes were assembled and analyzed with the BioEdit 2. Materials and methods Sequence Alignment Editor (Version 7.0.5.2). A phylogenetic analysis was performed using MEGA package (Version 3.1). 2.1. Patients and specimens Distances between sequences were analyzed using the neighbor- joining algorithm based on the Kimura two-parameters distance All rotavirus samples used were obtained from three studies estimative method for nucleotide (Kimura, 1980). Bootstrap previously conducted in Belem,´ Brazil, where P[6] genotypes resembling (over 2000 replicates). could be determined. The Study A involved diarrheic young Prototype strains for VP4 and NSP4 genes were obtained from children with ages ranging from 9 to 24 months, who partici- GenBank at the National Center for Biotechnology Information, pated in a trial with the Rhesus-human reassortant tetravalent USA (http://www.ncbi.nlm.nih.gov), through the conducting of rotavirus vaccine (RRV-TV), from 1990 to 1992 (Linhares et Blast and nucleotide search. al., 1996; Mascarenhas et al., 2002). The Study B was a surveil- lance for rotavirus infection from May 1996 to May 1998 among 3. Results neonates admitted to a hospital in Belem,´ Brazil (Linhares et al., 2002; Mascarenhas et al., 2006, 2007). The Study C was con- 3.1. Characterization of rotavirus strains by PAGE, PCR ducted among hospitalized young children with diarrhea and and sequence analysis those attending an outpatient health unit in a 2-year surveil- lance study in Belem,´ Brazil, conducted from May 1998 to May Fig. 1 shows the characteristics of 27 P[6] VP4 strains, includ- 2000 (Gabbay et al., 2002; Mascarenhas et al., 2003). Fig. 1 ing corresponding RNA profile, VP7 and NSP4 specificities. The summarizes the main characteristics of these studies. Overall, three strains from Study A were genotyped as G4 and NSP4 B. 27 samples were available in sufficient amount and were then Sixteen out of 17 strains from Study B displayed short electro- selected from the original studies, as follows: 3 from the Study pherotype and were genotyped as G2 and NSP4 A. A more A, 17 from Study B and 7 from Study C. The neonates and wide variation in electropherotypes, G and NSP4 genotypes diarrheic children lived in the outskirts of Belem,´ Brazil, under was observed in the Study C, which showed G2, G4 and G9 poor sanitation conditions and in close contact with domestic associated with either NSP4 A or B. animals, including pigs. 3.2. Comparison of amino acid sequence of VP8* gene 2.2. RT-PCR amplification of the VP4, VP7 and NSP4 from rotaviruses P[6] genotypes genes A phylogenetic tree was constructed using the deduced aa Rotavirus dsRNA was extracted from 10% fecal suspensions sequences of the VP4 protein (270 aa), corresponding to aa by using guanidinium isothiocyanate-silica nucleic acid extrac- 13–282 of the coding region of the gene (Fig.
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