PhD ceremony Ms. S.M. Torres Pedraza: Early events in Dengue virus infection

Dissertation: Early events in Dengue virus infection

Promotor(s): prof. J.M. Smit, prof. S. Urcuqui Inchima

Faculty: Medical Sciences

Dengue is the most prevalent mosquito-borne viral disease in the world. It is caused by an infection with any of the 5 dengue virus serotypes (DENV1-5) The infection can induce multiple clinical manifestations ranging from a self-limited febrile disease dengue fever to life-threatening hemorrhagic manifestations. DENV is considered an immunopathogenic since its infection can induce an exacerbated pro-inflammatory response, which hallmarks the severe disease. Presence of non-neutralizing dengue antibodies in early infection is considered one of the main risk for the development of severe disease.

DENV targets and replicates in the three major phagocytic cell types including dendritic cells (DCs). Studies presented in this thesis focus largely on the role that DCs play during DENV infection and how antibodies influence it. The key findings include our ex vivo data demonstrating that on the basis of the expression levels of pathogen recognition receptors called Toll-like receptors in DCs early in infection we might be able to predict the progress of disease. Furthermore, in vitro immature DCs have been found to be relatively refractory to DENV infection and produced poorly infectious virus. In the presence of neutralizing antibodies, infection of DCs caused their maturation and release of balanced inflammatory response. Infection in the presence of non-neutralizing antibodies however, lead to altered immature DCs activation, triggered mainly proinflammatory response, and it enhanced infection of mature DCs. Thus, we showed that DCs can play a dual role during dengue infection depending on their maturation state as well as on the presence and quality of the antibodies during initial contact with the virus.