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: ClinicalTrials.gov identifier: NCT04615364.
Acknowledgments
We warmly thank the Clinical Research Department of the Centre for Translational Research at Institut Pasteur in Paris for their support in ethic procedures. We thank Fabiana Gámbaro and Deborah Delaune for their contribution to whole-genome sequencing. We thank Ludivine Grzelak for her support in the implementation of in vitro replication kinetics. CI, ESL and MDR designed the research study; CI, MM, ESL, MP and OOC conducted the experiments; IM, CC, EKF, MS, AM, AB, ACG and ED collected and acquired data on patients; CF, AP, AT, CI, MM, ESL, MDR analysed the data; CI, wrote the manuscript; ESL and MDR edited the manuscript; all authors carefully revised the manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).