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IN SILICO ANALYSIS OF DENGUE VIRUS SEROTYPE 2 MUTATIONS DETECTED AT THE INTRAHOST LEVEL IN PATIENTS WITH DIFFERENT CLINICAL OUTCOMES
Mutações do sorotipo 2 do vírus da dengue
Detectado no Nível Intrahost
Pacientes
Diferentes Resultados clínicos
Dengue Virus Serotype 2 Mutations
Detected
Intrahost Level
Patients
Different Clinical Outcomes
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Flavivírus. Rio de Janeiro, RJ, Brasil.
Laboratório Nacional de Computação Científica. Grupo de Modelagem Molecular de Sistemas Biológicos. GMMSB/LNCC-MCTI, Petrópolis,, RJ, Brasil.
Laboratório Nacional de Computação Científica. Grupo de Modelagem Molecular de Sistemas Biológicos. GMMSB/LNCC-MCTI, Petrópolis,, RJ, Brasil.
Laboratório Nacional de Computação Científica. Grupo de Modelagem Molecular de Sistemas Biológicos. GMMSB/LNCC-MCTI, Petrópolis,, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Flavivírus. Rio de Janeiro, RJ, Brasil.
Laboratório Nacional de Computação Científica. Grupo de Modelagem Molecular de Sistemas Biológicos. GMMSB/LNCC-MCTI, Petrópolis,, RJ, Brasil.
Laboratório Nacional de Computação Científica. Grupo de Modelagem Molecular de Sistemas Biológicos. GMMSB/LNCC-MCTI, Petrópolis,, RJ, Brasil.
Laboratório Nacional de Computação Científica. Grupo de Modelagem Molecular de Sistemas Biológicos. GMMSB/LNCC-MCTI, Petrópolis,, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Flavivírus. Rio de Janeiro, RJ, Brasil.
Abstract
Intrahost genetic diversity is thought to facilitate arbovirus adaptation
to changing environments and hosts, and it may also be linked to viral pathogenesis.
Intending to shed light on the viral determinants for severe dengue pathogenesis,
we previously analyzed the DENV-2 intrahost genetic diversity in 68 patients clinically
classified as dengue fever (n = 31), dengue with warning signs (n = 19), and
severe dengue (n = 18), performing viral whole-genome deep sequencing from clinical
samples with an amplicon-free approach. From it, we identified a set of 141 relevant
mutations distributed throughout the viral genome that deserved further attention.
Therefore, we employed molecular modeling to recreate three-dimensional models
of the viral proteins and secondary RNA structures to map the mutations and assess
their potential effects. Results showed that, in general lines, disruptive variants were
identified primarily among dengue fever cases. In contrast, potential immune-escape
variants were associated mainly with warning signs and severe cases, in line with the
latter’s longer intrahost evolution times. Furthermore, several mutations were located on
protein-surface regions, with no associated function. They could represent sites of further
investigation, as the interaction of viral and host proteins is critical for both host
immunomodulation and virus hijacking of the cellular machinery. The present analysis
provides new information about the implications of the intrahost genetic diversity of
DENV-2, contributing to the knowledge about the viral factors possibly involved in its
pathogenesis within the human host. Strengthening our results with functional studies
could allow many of these variants to be considered in the design of therapeutic or prophylactic
compounds and the improvement of diagnostic assays.
Keywords in Portuguese
Análise in silicoMutações do sorotipo 2 do vírus da dengue
Detectado no Nível Intrahost
Pacientes
Diferentes Resultados clínicos
Keywords
In Silico AnalysisDengue Virus Serotype 2 Mutations
Detected
Intrahost Level
Patients
Different Clinical Outcomes
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