title: A genetic and pathologic study of a DENV2 clinical isolate capable of inducing encephalitis and hematological disturbances in immunocompetent mice.
abstract: Dengue virus (DENV) is the causative agent of dengue fever (DF), a mosquito-borne illness endemic to tropical and subtropical regions. There is currently no effective drug or vaccine formulation for the prevention of DF and its more severe forms, i.e., dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). There are two generally available experimental models for the study of DENV pathogenicity as well as the evaluation of potential vaccine candidates. The first model consists of non-human primates, which do not develop symptoms but rather a transient viremia. Second, mouse-adapted virus strains or immunocompromised mouse lineages are utilized, which display some of the pathological features of the infection observed in humans but may not be relevant to the results with regard to the wild-type original virus strains or mouse lineages. In this study, we describe a genetic and pathological study of a DENV2 clinical isolate, named JHA1, which is naturally capable of infecting and killing Balb/c mice and reproduces some of the symptoms observed in DENV-infected subjects. Sequence analyses demonstrated that the JHA1 isolate belongs to the American genotype group and carries genetic markers previously associated with neurovirulence in mouse-adapted virus strains. The JHA1 strain was lethal to immunocompetent mice following intracranial (i.c.) inoculation with a LD(50) of approximately 50 PFU. Mice infected with the JHA1 strain lost weight and exhibited general tissue damage and hematological disturbances, with similarity to those symptoms observed in infected humans. In addition, it was demonstrated that the JHA1 strain shares immunological determinants with the DENV2 NGC reference strain, as evaluated by cross-reactivity of anti-envelope glycoprotein (domain III) antibodies. The present results indicate that the JHA1 isolate may be a useful tool in the study of DENV pathogenicity and will help in the evaluation of anti-DENV vaccine formulations as well as potential therapeutic approaches.
authors.affiliation: Vaccine Development Laboratory, Department of Microbiology, University of São Paulo, Brazil.
authors.forename: Jaime Henrique
authors.initials: JH
authors.lastname: Amorim
authors.forename: Raíza Sales
authors.initials: RS
authors.lastname: Pereira Bizerra
authors.forename: Rúbens Prince
authors.initials: RP
authors.lastname: dos Santos Alves
authors.forename: Maria Elisabete
authors.initials: ME
authors.lastname: Sbrogio-Almeida
authors.forename: José Eduardo
authors.initials: JE
authors.lastname: Levi
authors.forename: Margareth Lara
authors.initials: ML
authors.lastname: Capurro
authors.forename: Luís Carlos
authors.initials: LC
authors.lastname: de Souza Ferreira
mesh_terms: D056704:Adaptive Immunity; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D003715:Dengue / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000821:virology*; D003716:Dengue Virus / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity* / Q000502:physiology; D004660:Encephalitis / Q000097:blood* / Q000150:complications / Q000276:immunology / Q000821:virology*; D006801:Humans; D007121:Immunocompetence / Q000276:immunology*; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010802:Phylogeny; D014764:Viral Proteins / Q000737:chemistry; D014771:Virion / Q000276:immunology; D014779:Virus Replication
chemical_list: D014764:Viral Proteins