Viral evolution sustains a dengue outbreak of enhanced severity

Abstract

Compared to the previous 2013–2014 outbreak, dengue 2016–2017 outbreak in New Caledonia was characterized by an increased number of severe forms associated with hepatic presentations. In this study, we assessed the virological factors associated with this enhanced severity. Whole-genome sequences were retrieved from dengue virus (DENV)-1 strains collected in 2013–2014 and from severe and non-severe patients in 2016–2017. Fitness, hepatic tropism and cytopathogenicity of DENV 2016–2017 strains were compared to those of 2013–2014 strains using replication kinetics in the human hepatic cell line HuH7. Whole-genome sequencing identified four amino acid substitutions specific to 2016–2017 strains and absent from 2013–2014 strains. Three of these mutations occurred in predicted T cell epitopes, among which one was also a B cell epitope. Strains retrieved from severe forms did not exhibit specific genetic features. DENV strains from 2016–2017 exhibited a trend towards reduced replicative fitness and cytopathogenicity in vitro compared to strains from 2013–2014. Overall, the 2016–2017 dengue outbreak in New Caledonia was associated with a viral genetic evolution which had limited impact on DENV hepatic tropism and cytopathogenicity. These mutations, however, may have modified DENV strains antigenicity, altering the anti-DENV immune response in some patients, in turn favoring the development of severe forms. Trial registration: .

Variability in Susceptibility to Type I Interferon Response and Subgenomic RNA Accumulation Between Clinical Isolates of Dengue and Zika Virus From Oaxaca Mexico Correlate With Replication Efficiency in Human Cells and Disease Severity

“…However, the variability of cocirculating flaviviruses is typically determined by comparing the genome sequence instead of the phenotype. It has been suggested that some strains of DENV and ZIKV could be associated with enhanced severity of outbreaks or epidemiological replacements, but the characterization of phenotypes that could explain these differences in transmissibility or virulence between Flavivirus variants is rarely explored ( Zhang et al., 2005 ; De Castro et al., 2013 ; Xia et al., 2018 ; Aubry et al., 2021 ; Inizan et al., 2021 ).…”

Clinical manifestations of dengue, Zika and chikungunya in the Pacific Islands: A systematic review and meta‐analysis

“…Lastly, the pooled prevalence estimate for severe forms of dengue (DHF, DSS or severe dengue) was 1.92% in the general population, with DHF estimated at 2.34% (95% CI 0.61–5.04) and severe dengue estimated at 1.10% (95% CI 0.39–2.14). The prevalence of these severe forms increased to 23.23% (95% CI 13.58–34.53) in hospitalised cohorts, with DHF prevalence estimated at 21.06% (95% CI 7.48–39.07), DSS estimated at 4.11% (95% CI 0.02–13.39) and one study reporting severe dengue in 24.64% of patients 51 . In both patient cohorts, no publication bias was detected and excluding one study at a time during sensitivity analysis did not alter effect size significantly apart from one study in the general population cohort 52 and another study in the cohort of hospitalised patients, 53 both of which reported significantly higher rates of DHF (see supplementary materials and for further details).…”

Identification of stage-related and severity-related biomarkers and exploration of immune landscape for Dengue by comprehensive analyses

“…Dengue was listed by the World Health Organization (WHO) as one of the top ten global health threats announced at the beginning of 2019 [1]. In the past few decades, Dengue has become the fastest-growing mosquito borne disease in the world [2][3][4], seriously endangering human health [5,6]. Vaccine research and development continue to make progress [7][8][9][10][11][12], but the antibody-dependent enhancement (ADE) limits the effectiveness of vaccines [13][14][15][16][17].…”