Phylodynamics of dengue virus 2 in Nicaragua leading up to the 2019 epidemic reveals a role for lineage turnover

Abstract

Background: Dengue is a mosquito-borne viral disease posing a significant threat to public health. Dengue virus (DENV) evolution is often characterized by lineage turnover, which, along with ecological and immunological factors, has been linked to changes in dengue phenotype affecting epidemic dynamics. Utilizing epidemiologic and virologic data from long-term population-based studies (the Nicaraguan Pediatric Dengue Cohort Study and Nicaraguan Dengue Hospital-based Study), we describe a lineage turnover of DENV serotype 2 (DENV-2) prior to a large dengue epidemic in 2019. Prior to this epidemic, Nicaragua had experienced relatively low levels of DENV transmission from 2014 to 2019, a period dominated by chikungunya in 2014/15 and Zika in 2016.

Results: Our phylogenetic analyses confirmed that all Nicaraguan DENV-2 isolates from 2018 to 2019 formed their own clade within the Nicaraguan lineage of the Asian/American genotype. The emergence of the new DENV-2 lineage reflects a replacement of the formerly dominant clade presiding from 2005 to 2009, a lineage turnover marked by several shared derived amino acid substitutions throughout the genome. To elucidate evolutionary drivers of lineage turnover, we performed selection pressure analysis and reconstructed the demographic history of DENV-2. We found evidence of adaptive evolution by natural selection at the codon level as well as in branch formation.

Conclusions: The timing of its emergence, along with a statistical signal of adaptive evolution and distinctive amino acid substitutions, the latest in the NS5 gene, suggest that this lineage may have increased fitness relative to the prior dominant DENV-2 strains. This may have contributed to the intensity of the 2019 DENV-2 epidemic, in addition to previously identified immunological factors associated with pre-existing Zika virus immunity.

Keywords: Clade replacement; Dengue virus; Lineage turnover; Natural selection; Nicaragua; Phylodynamics; Virus evolution.

Fig. 1

Confirmed arboviral cases caused by DENV, CHIKV or ZIKV in Nicaragua, 2004–2021

Fig. 2

Maximum likelihood (ML) phylogeny of DENV-2. Thirty-two newly sequenced genomes from Managua and León, Nicaragua, are shown in the clade colored magenta (samples from León are denoted by “LLE”). The enlarged tree on the right represents the phylogeny shaded gray in the tree in the upper left-hand corner. Sequences are labeled by ISO country code, sample identifier, and year of isolation. Bootstrap values are shown for each clade. Each black bar on the branches represents a clade-specific non-synonymous mutation

Fig. 3

Locations of non-synonymous mutations (cyan) associated with the evolution of NI-3B clade on a DENV-2 genome, with pr-E, NS1, and NS5 protein structures

Fig. 4

Bayesian skyline plot showing the relative effective population size of DENV-2 infections in the sampled population. The y-axis represents the effective number of infections in log₁₀ scale. The x-axis represents the year. The thick blue line represents the median estimate, and the credibility interval based on 95% HPD interval is represented by thin blue lines