Non-neutralizing Antibodies in the Complex Dance of Dengue Clearance and Immune Avoidance

Abstract

Dengue virus (DENV) is endemic in over 100 countries causing widespread morbidity and mortality. Approximately 400 million people are infected annually with one of the four immunologically and genetically distinct serotypes of DENV, resulting in 100 million symptomatic cases and at least 40,000 deaths. While the mechanisms behind the pathophysiology of severe DENV infection are complex and incompletely understood, it has been previously suggested that antibodies directed against the DENV envelope (E) protein can facilitate antibody dependent enhancement (ADE) of the virus during secondary DENV infections, increasing the number of infected cells and the clinical severity of infection in an exposed individual. However, there are other functional roles for antibodies outside neutralization of the virion. In this thesis, we describe the roles of non-neutralizing antibodies during DENV-infection. We show that IgG and IgA non-structural protein 1 (NS1)- and E-reactive antibodies are capable of mediating monocytic phagocytosis of DENV-infected cells. We show that secreted NS1 (sNS1) acts as immunological chaff and abrogates NS1-reactive antibody-mediated phagocytosis. We also begin to investigate the potential of phagocytosis of DENV-infected cells to lead to lead to infection of phagocytic monocytes. The findings described in these studies have implications in therapeutics and vaccinations targeting both NS1 and E protein.