Evasion of human front-line defences as a determinant of Dengue-2 pathogenesis

Dengue virus (DNV) is the most prevalent mosquito-transmitted human virus. Approximately 4 billion people live in areas with circulating DNV and over 300 million are annually infected. In addition, climate change has broadened DNV range beyond tropical areas, including Europe.

DNV usually causes mild-to-no-disease, but some patients develop severe dengue for which no effective treatments are available and mortality is up to 20%. Both viral and host factors contribute to severe dengue.

Viral factors include unexplained differences in pathogenicity across DNV-1-4 serotypes, where DNV-2 is the most pathogenic and associated with more severe disease, as well as multi-serotype infections that also risk severe disease through antibody dependent enhancement (ADE).

Host risk factors include comorbidities and genetic defects in front-line antiviral defences, named restriction factors.

However, the repertoire of restriction factors that inhibit DNV replication and their impact on DNV pathogenesis remain poorly understood. Using a genome-wide genetic screen, I recently identified 264 human restriction factors that inhibit DNV-3.

In this award, I will identify which of these restriction factors are serotype-specific and which target all four DNV serotypes (Objective 1).

Moreover, my preliminary data suggests that the more pathogenic DNV-2 can evade host restriction factors that are functional against DNV-3, and so I will define DNV-2 proteins that enable evasion from restriction factors (Objective 2).

Critically, the results from this proposal will lead to a significant shift in our understanding of DNV control and identify potential determinants of pathogenesis that can inform the future development of much needed DNV therapeutics.