Abstract
The exact mechanisms of interplay between host and viral factors leading to severe dengue are yet to be fully understood. Even though previous studies have implicated specific genetic differences of Dengue virus (DENV) in clinical severity and virus attenuation, similar studies with large-scale, whole genome screening of monophyletic virus populations are limited. Therefore, in the present study, we compared 89 whole genomes of DENV-2 cosmopolitan clade III isolates obtained from patients diagnosed with dengue fever (DF, n = 58), dengue hemorrhagic fever (DHF, n = 30) and dengue shock syndrome (DSS, n = 1) in Singapore between July 2010 and January 2013, in order to determine the correlation of observed viral genetic differences with clinical outcomes. Our findings showed no significant difference between the number of primary and secondary infections that progressed to DHF and DSS (p>0.05) in our study cohort. Despite being highly homogenous, study isolates possessed 39 amino acid substitutions of which 10 substitutions were fixed in three main groups of virus isolates. None of those substitutions were specifically associated with DHF and DSS. Notably, two evolutionarily unique virus groups possessing C-P43T+NS1-S103T+NS2A-V83I+NS3-R337K+ NS3-I600T+ NS5-P136S and NS2A-T119N mutations were exclusively found in patients with DF, the benign form of DENV infections. Those mutants were significantly associated with mild disease outcome. These observations indicated that disease progression into DHF and DSS within our patient population was more likely to be due to host than virus factors. We hypothesize that selection for potentially less virulent groups of DENV-2 in our study cohort may be an evolutionary adaptation of viral strains to extend their survival in the human-mosquito transmission cycle.
Highlights
Dengue fever is the most widespread arbovirus disease at present with an annual estimate of 50 million infections worldwide [1]
In the present study, we compared 89 whole genomes of Dengue virus (DENV)-2 cosmopolitan clade III isolates obtained from patients diagnosed with dengue fever (DF, n = 58), dengue hemorrhagic fever (DHF, n = 30) and dengue shock syndrome (DSS, n = 1) in Singapore between July 2010 and January 2013, in order to determine the correlation of observed viral genetic differences with clinical outcomes
Our findings indicated that subtle genetic differences in a highly homogenous, monotypic DENV-2 population potentially modified the clinical outcome of our study subjects, regardless of primary and secondary infection status
Summary
Dengue fever is the most widespread arbovirus disease at present with an annual estimate of 50 million infections worldwide [1]. The disease is caused by Dengue virus (DENV) complex that consists of four genetically and immunogenically distinct serotypes (DENV-1 to DENV-4). Most DENV infections are benign and manifest either sub-clinically or as a flu-like illness known as dengue fever (DF). Being a RNA virus, DENV undergoes a rapid evolutionary process [3, 4], generating substantial genetic diversity (genotypes) within each serotype [4]. The evolutionary process of DENV selects for strains with enhanced adaptation, resulting in mutant variants that differ in their ability to spread and cause disease [3, 5]. All four DENV serotypes are capable of causing severe dengue clinically [6]. Even though the clinical outcome of DENV infections is dependent on host and viral factors, the mechanism of their interplay leading to severe disease is not fully understood. Role of virus genetics in determining the virulence of natural virus populations is sparsely characterized
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