Quantifying temporal differences in the induction of interferon-mediated signalling observed in a dengue virus 1 human infection model: insights from longitudinal proteome analysis.

BACKGROUND

According to WHO, dengue is one of the top ten global health threats, with almost half of the world's population at risk of being infected. Most of the annual 400 million dengue virus (DENV) infections manifest asymptomatically or in a mild form, causing symptoms such as fever and headache. Nevertheless, every year 500,000 dengue cases require hospitalization and up to 25,000 patients die. Despite the high incidence, the DENV-elicited proteome response remains insufficiently understood.

METHODS

Therefore, we evaluated the proteome dynamics of nine dengue-naïve individuals experimentally infected with the underattenuated DENV-1 strain 45AZ5 via the Proximity Extension Assay technology of Olink®.

FINDINGS

Using Olink Explore, a total of ∼3000 proteins were quantified simultaneously in serum samples at 8, 10, 14, and 28 days after the viral inoculation. We identified the top ten significant proteins via linear mixed effects models, i.e., interferons (IFNs), IFN-related proteins, and members of the CCL and CXCL chemokine family. In all participants, an increase in IFN-λ1 levels was observed after peak viral load, whereas in one participant an IFN-γ response was not detected. Interestingly, both the onset and peak viral load of this participant were, on average, delayed 4 days compared to other participants. To gain a detailed kinetic overview of the DENV-elicited proteome response, we designed a smaller, targeted Olink® panel to evaluate serum protein levels at multiple time points throughout the infection. Here, we revealed that type I/III IFN response precedes the type II IFN response.

INTERPRETATION

In conclusion, our analyses provided detailed insights into the temporal dynamics of the different IFN responses upon a primary DENV-1 infection. These insights might aid in better understanding dengue pathogenesis.

FUNDING

Funding for this research was provided by Johnson and Johnson, the State of New York, and the Congressionally Directed Medical Research Programs.