title: Clinical outcome and genetic differences within a monophyletic Dengue virus type 2 population.
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.
authors: Environmental Health Institute, National Environment Agency, 11 Biopolis Way, #06-05-08, Singapore 138667.
authors: Hapuarachchige Chanditha
authors: HC
authors: Hapuarachchi
authors: Environmental Health Institute, National Environment Agency, 11 Biopolis Way, #06-05-08, Singapore 138667.
authors: Rachel Choon Rong
authors: RC
authors: Chua
authors: Environmental Health Institute, National Environment Agency, 11 Biopolis Way, #06-05-08, Singapore 138667.
authors: Yuan
authors: Y
authors: Shi
authors: Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433.
authors: Tun Lin
authors: TL
authors: Thein
authors: Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433.
authors: Linda Kay
authors: LK
authors: Lee
authors: School of Life Sciences and Chemical Technology, Ngee Ann Polytechnic, 535 Clementi Road, Singapore 599489.
authors: Kim Sung
authors: KS
authors: Lee
authors: Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433.
authors: David Chien
authors: DC
authors: Lye
authors: Environmental Health Institute, National Environment Agency, 11 Biopolis Way, #06-05-08, Singapore 138667.
authors: Lee Ching
authors: LC
authors: Ng
authors: Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433.
authors: Yee Sin
authors: YS
authors: Leo
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D015331:Cohort Studies; D003715:Dengue / Q000276:immunology / Q000821:virology*; D003716:Dengue Virus / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010802:Phylogeny; D012367:RNA, Viral / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D012367:RNA, Viral