Application of Next-Generation Sequencing to Reveal How Evolutionary Dynamics of Viral Population Shape Dengue Epidemiology

Abstract

Dengue viral (DENV) infection results in a wide spectrum of clinical manifestations from asymptomatic, mild fever to severe hemorrhage diseases upon infection. Severe dengue is the leading cause of pediatric deaths and/or hospitalizations, which are a major public health burden in dengue-endemic or hyperendemic countries. Like other RNA viruses, DENV continues to evolve. Adaptive mutations are obscured by the major consensus sequence (so-called wild-type sequences) and can only be identified once they become the dominant viruses in the virus population, a process that can take months or years. Traditional surveillance systems still rely on Sanger consensus sequencing. However, with the recent advancement of high-throughput next-generation sequencing (NGS) technologies, the genome-wide investigation of virus population within-host and between-hosts becomes achievable. Thus, viral population sequencing by NGS can increase our understanding of the changing epidemiology and evolution of viral genomics at the molecular level. This review focuses on the studies within the recent decade utilizing NGS in different experimental and epidemiological settings to understand how the adaptive evolution of dengue variants shapes the dengue epidemic and disease severity through its transmission. We propose three types of studies that can be pursued in the future to enhance our surveillance for epidemic prediction and better medical management.

Genetic Variation in the Domain II, 3′ Untranslated Region of Human and Mosquito Derived Dengue Virus Strains in Sri Lanka

“…No such sequence variations were observed in the domain II, 3 UTR of DENV3 and DENV1 sequences identified in the current study and the human-and mosquito-derived sequences in the domain II, 3 UTR were identical in their respective serotypes (Table 1). However, adaptive mutations within the minor DENV populations within each host are known to be obscured by wild-type sequences and only revealed once they become dominant in the virus population and deep sequencing experiments are warranted to inference further in this regard [60]. The present study confirmed the reportedly high conservation of the RCS2 and CS2 regions in domain II, 3 UTR as shown by de Castro et al [55] in is his study of human-and mosquito-derived samples [55].…”

Dengue Virus Serotype 2 Intrahost Diversity in Patients with Different Clinical Outcomes

“…Several investigations showed evidence of a strong association between the genetic composition of intrahost viral populations and viral fitness and pathogenicity [ 9 , 10 , 11 , 12 ], especially lately that high-coverage and accurate whole-genome sequencing provided proof that fitness and adaptability variations occur without changes in the viral consensus sequence [ 19 , 20 , 50 ]. However, as recently reviewed by Ko et al, few studies tracked intrahost DENV diversity under epidemiological settings [ 19 , 20 , 50 , 51 ]. All of them combined viral genome PCR amplification + deep sequencing experimental strategies.…”

The effects of DENV serotype competition and co-infection on viral kinetics in Wolbachia-infected and uninfected Aedes aegypti mosquitoes

“…Substantial evidence indicates that variation in the DENV genome of serotypes and strains can have epidemiological significance by altering the extrinsic incubation period (EIP) [ 5 – 7 ], defined as the time it takes for the pathogen to be transmitted by the vector [ 8 ], and therefore has a powerful effect on the scale and speed of epidemics. DENV-2 strains from the American and Southeast Asian genotypes differ in their EIP lengths, with the Southeast Asian genotypes having shorter EIPs.…”