Dengue virus (DENV) is the leading cause of arthropod transmitted disease worldwide, with an estimated 2.5 billion individuals at risk for infection each year in tropical and subtropical areas. There are four serotypes of DENV which are transmitted by the mosquito Aedes aegypti and Aedes albopictus. Although DENV infections are asymptomatic, dengue disease can present as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). There are several hypotheses as to explain differences in disease severity. This thesis investigates the contribution of intrinsic viral factors to the innate immune response in primary immune cells utilizing clinical isolates of DENV-3 from Sri Lanka before and after the emergence of DHF in 1989. Using these clinical isolates we analyzed their replication and innate immune phenotype in a primary human system. Our data shows an increase in interferon (IFN) and IFN-stimulated gene induction only in dendritic cells (DCs) infected with post-DHF DENV-3, compared to the pre-DHF DENV-3. Co-culture experiments reveal that DCs infected with post-DHF DENV-3 prime T cells more efficiently towards Th1 responses than DCs infected with pre-DHF DENV-3. DCs infected with post-DHF DENV-3 also undergo apoptosis at higher levels in an IFN dependent manner compared with DCs infected with pre-DHF DENV-3. Current work investigates specific mutations in the DENV NS2B3 and NS5 genes may correspond to some of the observed differences in virulence between the viruses.
Secondly, as human-to-human transmission is very rare, this thesis examines the contribution of the vector to the immune response against DENV. We investigated the innate immune response in primary cells to DENV grown in a variety of mammalian cells (primary and cell lines) in addition to DENV grown in mosquito cells and whole mosquitos. Although we do not observe a significant difference in DENV grown in mammalian cells, dendritic cells infected with mosquito DENV express higher levels of pro-inflammatory cytokines at early time points after infection. Dendritic cells treated with mosquito homogenate also upregulated these cytokines suggesting that upregulation of proinflammatory cytokines could be caused by a mosquito factor. Future experiments will examine immune responses to individual mosquito salivary factor proteins.
|Advisor:||Sesma, Ana Fernandez|
|Commitee:||Evans, Matthew J., Simon, Viviana, Tortorella, Domenico, White, Laura|
|School:||Icahn School of Medicine at Mount Sinai|
|School Location:||United States -- New York|
|Source:||DAI-B 75/01(E), Dissertation Abstracts International|
|Keywords:||Aedes aegypti, Dendritic cells, Dengue hemorrhagic fever, Dengue virus, Innate immunity, Transmission|
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