title: Determinants of bluetongue virus virulence in murine models of disease.
abstract: Bluetongue is a major infectious disease of ruminants that is caused by bluetongue virus (BTV). In this study, we analyzed virulence and genetic differences of (i) three BTV field strains from Italy maintained at either a low (L strains) or high (H strains) passage number in cell culture and (ii) three South African "reference" wild-type strains and their corresponding live attenuated vaccine strains. The Italian BTV L strains, in general, were lethal for both newborn NIH-Swiss mice inoculated intracerebrally and adult type I interferon receptor-deficient (IFNAR(-/-)) mice, while the virulence of the H strains was attenuated significantly in both experimental models. Similarly, the South African vaccine strains were not pathogenic for IFNAR(-/-) mice, while the corresponding wild-type strains were virulent. Thus, attenuation of the virulence of the BTV strains used in this study is not mediated by the presence of an intact interferon system. No clear distinction in virulence was observed for the South African BTV strains in newborn NIH-Swiss mice. Full genomic sequencing revealed relatively few amino acid substitutions, scattered in several different viral proteins, for the strains found to be attenuated in mice compared to the pathogenic related strains. However, only the genome segments encoding VP1, VP2, and NS2 consistently showed nonsynonymous changes between all virulent and attenuated strain pairs. This study established an experimental platform for investigating the determinants of BTV virulence. Future studies using reverse genetics will allow researchers to precisely map and "weight" the relative influences of the various genome segments and viral proteins on BTV virulence.
authors.affiliation: Medical Research Council-University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Caporale
authors.forename: Rachael
authors.initials: R
authors.lastname: Wash
authors.forename: Attilio
authors.initials: A
authors.lastname: Pini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Savini
authors.forename: Paola
authors.initials: P
authors.lastname: Franchi
authors.forename: Matthew
authors.initials: M
authors.lastname: Golder
authors.forename: Janet
authors.initials: J
authors.lastname: Patterson-Kane
authors.forename: Peter
authors.initials: P
authors.lastname: Mertens
authors.forename: Luigina
authors.initials: L
authors.lastname: Di Gialleonardo
authors.forename: Gisella
authors.initials: G
authors.lastname: Armillotta
authors.forename: Rossella
authors.initials: R
authors.lastname: Lelli
authors.forename: Paul
authors.initials: P
authors.lastname: Kellam
authors.forename: Massimo
authors.initials: M
authors.lastname: Palmarini
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001819:Bluetongue / Q000473:pathology* / Q000821:virology*; D001820:Bluetongue virus / Q000302:isolation & purification / Q000472:pathogenicity*; D004195:Disease Models, Animal; D016679:Genome, Viral; D007558:Italy; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency; D012376:Rodent Diseases / Q000473:pathology / Q000821:virology; D017422:Sequence Analysis, DNA; D012692:Serial Passage; D016019:Survival Analysis; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics*
chemical_list: C508032:Ifnar1 protein, mouse; D037521:Virulence Factors; D053633:Receptor, Interferon alpha-beta