Combined diagnostic and prognostic test to improve dengue surveillance and patient monitoring

"IMMUNOBIOLOGY AND PROGNOSTIC POTENTIAL OF A PRO-INFLAMMATORY COMPLEX FORM OF THE DENGUE VIRUS NS1 LIPOPROTEIN Dengue (DEN) is a major vector-borne viral disease of the tropics. Dengue infections can be asymptomatic in a significant number of cases. However, when symptoms do occur, they can range from mild, flu-like illness to severe dengue, most often requiring hospitalization. In humans, severe clinical manifestations are characterized by signs of hemorrhage and a life-threatening hypovolemic shock. Dengue virus encodes the NS1 protein, an accessory protein that is secreted from dengue virus (DENV)-infected cells. Extracellular NS1 has been shown by our group and others to alter the complement system, activate immune cells, trigger plasma leakage and enhance virus production. We recently showed that NS1 binds endogenous high-density lipoprotein (HDL) and to a lower extent low-density lipoprotein (LDL) particles in plasma. The NS1-HDL lipoprotein complex represents a potent bioactive form of the viral protein and a potent modulator of inflammation. Highjacking HDL, which are key players of vasculo-endothelial homeostasis, likely represents a key determinant for the virus to alter biological barriers and invade the infected host. The main aim of the present project is to challenge the relevance of our NS1 findings in the context of natural DENV infections. We will monitor the levels of NS1 and NS1-lipoprotein complexes in plasma from mild and severe dengue cases and in vaccinated individuals, define the prognostic value of NS1-lipoprotein complexes, study their protein and lipid composition, and finally explore the antibody response against NS1, human lipoproteins and their possible adverse autoimmune nature. This project brings together research teams with decades of research expertise in dengue virus and other arbovirus infections in human populations and a strong background in both basic and translational science. The project will benefit from an access to DENV-infected patient cohorts available in Argentina and Cambodia, where dengue epidemics frequently strike and represent a major health burden. Overall, we will address the following questions: Can the detection of NS1-lipoprotein complexes aid in the prediction of severe dengue? Do the NS1-lipoprotein complexes contribute to the cytokine-mediated inflammatory process? Are autoantibodies generated against the NS1-bound human HDL and LDL liprotein particles during DEN infections? What are the acute and long-term consequences of these different pathobiological events? This collaborative network represents a unique opportunity to investigate the role of NS1 in the pathobiology of DENV infection and the mechanisms underlying both natural and vaccine-induced immunity against NS1-lipoprotein complexes. We expect this study to increase our knowledge on the critical determinants of severe dengue, improve dengue surveillance and meet important needs for the management of hospitalized patients. Finally, the collaboration among the three research laboratories, will allow us to work with samples from dengue patients that were infected with different serotypes or genotypes. This will provide a more comprehensive understanding of the virus, which is crucial for vaccine development, outbreak prediction, and effective public health interventions."