F. Anfasa

Arboviruses are a group of viruses that are transmitted through the bites of mosquitoes and/or ticks. During the past decades, ZIKV, DENV, and CHIKV have (re-)emerged as arboviruses of increasing medical importance. Severe clinical manifestations and complications due to ZIKV, DENV, and CHIKV infections are the results of a complex interaction between viral and host factors. There are limited markers of disease severity available for these virus infections. This thesis describes studies of viral and host markers that are associated with disease severity for ZIKV, DENV, and CHIKV infections.

We observed phenotypic differences between ZIKV Asian and African strains, which could be one of the possible reasons of the severe neurological complications detected in humans in the recent epidemics. Our study illustrates the importance of using appropriate viral strains to study the pathogenesis of ZIKV infection and develop novel intervention strategies. We also demonstrated that ZIKV infection induces apoptosis and increase TF expression on endothelial cell (EC). This might be one of the reasons of vasculopathy observed in several animal models and humans.

We provide evidence that microbial translocation (MT), immune mediators, and EC activation markers were mainly elevated in the critical phase (CP) and are associated with vascular leakage in a cohort of dengue patients. We also identified associations between serum MT markers and inflammatory and EC markers. This suggests that translocation likely contribute to immune activation in the CP of dengue. Thus, therapeutic modalities targeting MT pathway may be an intervention strategy against severe dengue. In addition, we also identified a protein, endocan, which has the potential to be used as a surrogate marker of vascular leakage in clinical practice.

We found that elevated ferritin levels are significantly associated with viremia and chronic chikungunya disease. It is known that macrophages are one of the most important sources of ferritin during inflammatory disease. Moreover, macrophages are one of the primary target cells for CHIKV. Our study suggests that ferritin may serve as a potential prognostic marker for development of chronic chikungunya disease. We also found that neutralizing antibody titer solely seems insufficient to protect against the development of chronic chikungunya. Nevertheless, we observed that patients with acute disease had a significantly higher antibody avidity index compared to patients with chronic disease. Thus, better understanding of the antibody profile may be important to better comprehend the association of neutralizing antibodies and chronic chikungunya disease, which may be important for vaccine design and other related therapeutic strategies.

Collectively, we found several potential markers that are associated with severe disease manifestations of the three arboviruses addressed in this thesis. A better understanding of the role of these biomarkers in disease pathogenesis is warranted to instigate the development of novel intervention strategies against novel arboviruses.