Exploration and Manipulation of Micro-RNA Expression on the Immunopathogenesis of Dengue Antibody-Dependent Enhancement

Dengue hemorrhagic fever (DHF) is a potentially fatal disease threatening two-thirds of the global countries, including Taiwan. Evidence has shown that a sequentially heterotypic dengue (DEN) infections may induce an immune augmentation, resulting in higher frequency of DHF. It is believed that presence of heterotypic dengue antibody can enhance secondary dengue infection to leukocytes, especially monocytes and dendritic cells, resulting in augmentation of immune reaction that causes over production of immune mediators for vascular leakage, platelet consumption, and hemorrhage. Epidemiological studies in southern Taiwan have shown that DEN-1 had been prevalent in the past decade, and a mixed prevalence of DEN-2, DEN-3 and DEN-4 has been found in recent years. It has been concerned whether serious outbreak of DHF may happen very soon. Currently, there is no safe dengue vaccine available and there is no useful animal model suitable for pursuing pathogenesis of DHF. We have previously developed an in vitro model to simultaneously monitor dengue virus load and immune reactions in dengue infections, and demonstrated that presence of heterotypic dengue antibodies enhanced IL-10 production but suppressed IFNγ production by human mononuclear cells (Yang et al. J Med Virol 63:150-157, 2001). In a recent DEN-2 outbreak, we validated that patients with DHF did not have higher virus titers than those with dengue fever, but altered T helper 2 (Th2) mediator (Chen & Yang et al. Trans R Soc Trop Med Hyg 101:1106-13, 2007), and cytokine receptor expression (Wang & Yang et al. Am J Trop Med Hyg 77:297-302, 2007). Extending from these results, we hypothesize that DHF with antibody enhancement of DEN infections may have a fundamental alteration of microRNA expression that modulates mRNA expression and protein translation, resulting in augmented Th2 response and cytokine production. Based on this hypothesis, we attempt to use exogenous anti-DEN-1 antibody to mimic antibody enhancement of DEN-2 infection in human mononuclear cells and explore what and how miRNA are involved in DHF and antibody-dependent enhancement of Th2 cytokine production. Specifically, we aim to investigate the following objectives: 1) To testify whether patients with and without DHF have different miRNA expressing profiles in innate and adaptive immune cells. These abnormal profiles will be validated by an ex vivo simulation of anti-DEN-1 antibody enhancement of DEN-2 infections. 2) Based on the abnormal miRNA profile in innate immunity cells, our specific aim 2 is to target the abnormality of antibody-dependent enhancement of Th2 reaction and cytokine production in monocytes and dendritic cells by using miRNA precursor(s) or antagomir(s). 3) Specific aim 3 is to manipulate the abnormality of miRNA expression on the DEN-1 antibody enhancement of DEN-2 infections in adaptive immunity cells such as CD4 T cells to correct the augmented Th2 response and cytokine production by using miRNA precursor(s). Results from the clinical-orientated miRNA alteration to fundamental correction of the altered Th2 reaction in the heterotypic antibody enhancement of dengue infections will be validated in patients with and without DHF. After validation, the results may be able to translate into clinical applications for early prediction of DHF by miRNA profiles, and possibly suitable for therapeutic interventions with miRNA precursor(s) or antagomirs.

Project ID:PC9709-0932
External Project ID:NSC97-2628-B182-001-MY3