CONTRIBUTION OF MONOCYTE-DERIVED DENDRITIC CELLS INFECTED WITH VIRULENT- OR ATTENUATED-DENGUE VIRUS TO TNF-alpha REACTOGENICITY AND ASSOCIATION OF IL-1 beta AND IL-8 WITH ATTENUATED PHENOTYPE

Pathogenesis of severe dengue is partially known and involves virus and immunologic factors in orchestrating the disease severity. While serving as principal innate immune cells, dendritic cells (DCs) sub-serve as target cells for dengue virus (DENV) proliferation. Accordingly, responses of DCs toward DENV are critical for protection or disease development. We compared levels of innate cytokines secreted from primary human monocyte-derived (Mo)DCs upon infection with virulent parental strains DENV-2 16681 and DENV-3 16562, to those of MoDCs infected with their respective attenuated strains, DENV-2 PDK53 and DENV-3 PGMK30. Productions of IL-1 beta and IL-8 are significantly upregulated in attenuated-DENV-infected MoDCs compared to those infected with their respective parental virulent viruses. Moreover, both virulent parental viruses were potent inducers of IL-10 and TNF-alpha. Interestingly, although attenuated DENV-2 PDK 53 was a poor inducer of TNF-alpha, reactogenic-attenuated DENV-3 PGMK30 induced TNF-alpha production to a level similar to that induced by its virulent parental strain, suggesting a contribution of TNF-alpha towards the reactogenicity of DENV-3 PGMK30. These observations indicate MoDCs are able to differentiate between infection from virulent and attenuated DENV and should provide important knowledge on dengue pathogenesis useful for vaccine development.