RESUMO
We performed whole-genome sequencing with bait enrichment techniques to analyze Andes virus (ANDV), a cause of human hantavirus pulmonary syndrome. We used cryopreserved lung tissues from a naturally infected long-tailed colilargo, including early, intermediate, and late cell culture, passages of an ANDV isolate from that animal, and lung tissues from golden hamsters experimentally exposed to that ANDV isolate. The resulting complete genome sequences were subjected to detailed comparative genomic analysis against American orthohantaviruses. We identified four amino acid substitutions related to cell culture adaptation that resulted in attenuation of ANDV in the typically lethal golden hamster animal model of hantavirus pulmonary syndrome. Changes in the ANDV nucleocapsid protein, glycoprotein, and small nonstructural protein open reading frames correlated with mutations typical for ANDV strains associated with increased virulence in the small-animal model. Finally, we identified three amino acid substitutions, two in the small nonstructural protein and one in the glycoprotein, that were only present in the clade of viruses associated with efficient person-to-person transmission. Our results indicate that there are single-nucleotide polymorphisms that could be used to predict strain-specific ANDV virulence and/or transmissibility. IMPORTANCE Several orthohantaviruses cause the zoonotic disease hantavirus pulmonary syndrome (HPS) in the Americas. Among them, HPS caused by Andes virus (ANDV) is of great public health concern because it is associated with the highest case fatality rate (up to 50%). ANDV is also the only orthohantavirus associated with relatively robust evidence of person-to-person transmission. This work reveals nucleotide changes in the ANDV genome that are associated with virulence attenuation in an animal model and increased transmissibility in humans. These findings may pave the way to early severity predictions in future ANDV-caused HPS outbreaks.
Assuntos
Síndrome Pulmonar por Hantavirus , Orthohantavírus , Cricetinae , Animais , Humanos , Orthohantavírus/genética , Síndrome Pulmonar por Hantavirus/genética , Mesocricetus , Modelos Animais , Genoma ViralRESUMO
Hantavirus cardiopulmonary syndrome is a severe human disease associated with hantavirus infection. The clinical course of illness varies greatly among individuals, possibly due to viral and immunological elements and the influence of host genetic factors on clinical outcome. As the magnitude of immune activation has been associated with disease severity, polymorphisms in genes involved in the immune response that may affect the development of this syndrome were investigated. Polymorphisms in the TGF-ß, IL-10, IL-6, and IFN-γ genes, human leukocyte antigens (HLA), and human platelet alloantigens (HPA) genes were investigated in 122 patients with Araraquara virus infection from Ribeirão Preto, Brazil. Patients were divided into two groups: hantavirus cardiopulmonary syndrome (HCPS group; n = 26) and hantavirus seropositive only (n = 96). The frequencies of HLA alleles, cytokines and platelet antigen genotypes were evaluated in both groups and compared to a control group. The data demonstrated no significant influence of the HLA alleles, HPA, IL-6, and IL-10 genotypes on susceptibility to hantavirus infection. However, the hantavirus seropositive group presented a significantly higher frequency of a polymorphism associated with a high IFN-γ production than the HCPS group. In addition, a genotype associated with high TGF-ß production was found more frequently in individuals infected with hantavirus than in the control group. This phenotype was associated with a less intense thrombocytopenia in the HCPS group and may be protective against the most severe form of hantavirus disease. More studies are required to quantify further the influence of the high TGF-ß producer phenotype on the outcome of hantavirus infection.
Assuntos
Antígenos de Plaquetas Humanas/genética , Citocinas/genética , Antígenos HLA/genética , Síndrome Pulmonar por Hantavirus/genética , Polimorfismo Genético , Adolescente , Adulto , Brasil , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Paraná state presents the fourth highest number of accumulated cases of hantavirus pulmonary syndrome in Brazil. To map the risk areas for hantavirus transmission we carried out a study based on rodent trapping and determined the anti-hantavirus seroprevalence in these animals and in the inhabitants of these localities. Overall seroprevalence in rodents and humans were 2.5% and 2.4%, respectively. Eighty-two percent of the seropositive rodents were genetically analyzed. Phylogenetic analyses revealed that hantaviruses from rodent samples cluster with Araucária (Juquitiba-like) or Jaborá hantavirus genotypes. The Jaborá strain was identified in Akodon serrensis and Akodon montensis, whereas the Araucária strain was detected in Oligoryzomys nigripes, Oxymycterus judex, A. montensis, and Akodon paranaensis, with the latter species being identified for the first time as a natural host. These findings expose the complex relationships between virus and reservoirs in Brazil, which could have an impact on hantavirus transmission dynamics in nature and human epidemiology.
Assuntos
Ecossistema , Síndrome Pulmonar por Hantavirus/veterinária , Síndrome Pulmonar por Hantavirus/virologia , Orthohantavírus/isolamento & purificação , Doenças dos Roedores/virologia , Adulto , Animais , Anticorpos Antivirais/sangue , Brasil/epidemiologia , Estudos Transversais , Genótipo , Orthohantavírus/genética , Síndrome Pulmonar por Hantavirus/epidemiologia , Síndrome Pulmonar por Hantavirus/genética , Humanos , Filogenia , RNA Viral/química , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária , Doenças dos Roedores/epidemiologia , Roedores , Estudos SoroepidemiológicosRESUMO
Activation of the immune response in hantavirus cardiopulmonary syndrome (HCPS) leads to a high TNF production, probably contributing to the disease. The polymorphic TNF2 allele (TNF -308G/A) has been associated with increased cytokine production. We investigated the association of the TNF2 allele with the outcome of hantavirus infection in Brazilian patients. A total of 122 hantavirus-exposed individuals (26 presenting HCPS and 96 only hantavirus seroconversion) were studied. The TNF2 allele was more frequently found in HCPS patients than in individuals with positive serology for hantavirus but without a history of HCPS illness, suggesting that the TNF2 allele could represent a risk factor for developing HCPS.
Assuntos
Infecções por Hantavirus/genética , Síndrome Pulmonar por Hantavirus/genética , Cardiopatias/genética , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Idoso , Brasil , Feminino , Predisposição Genética para Doença , Infecções por Hantavirus/virologia , Síndrome Pulmonar por Hantavirus/virologia , Cardiopatias/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome , Adulto JovemRESUMO
Hantaviruses are emerging viruses in the Americas that cause cardiopulmonary syndrome with high lethality. The intense cellular immune response to hantavirus alters normal endothelial cell barrier functions and seems to be harmful to the host. On the other hand, the humoral immune response seems to be essential for recovery from infection.