Innate Immune Responses in Human Dendritic Cells Upon Infection by Chimeric Yellow-Fever Dengue Vaccine Serotypes 1–4

Abstract

Dengue infection is an important public health issue worldwide. The ChimeriVax-Dengue (CYD) vaccine uses yellow fever (YF) 17D vaccine as a live vector. Dendritic cells (DCs) play a key role in initiating immune responses and could be an important primary target of dengue infection. We investigated in vitro the consequences of CYD infection of DCs on their activation/maturation and cytokine production. In CYD-infected DCs, we observed an up-regulation of HLA-DR, CD80, CD86, and CD83. Cells exposed to CYD secreted type I interferons, monocyte chemoattractant protein 1 (MCP-1)/CC chemokine ligand 2 (CCL-2), interleukin-6 (IL-6), and low amounts of tumor necrosis factor-alpha (TNF-alpha), but no IL-10, IL-12, or IL-1alpha. Parental dengue viruses induced a similar array of cytokines, but more TNF-alpha, less IL-6, and less MCP-1/CCL-2 than induced by CYD. Chimeras thus induced DCs maturation and a controlled response accompanied by limited inflammatory cytokine production and consistent expression of anti-viral interferons, in agreement with clinical observations of safety and immunogenicity.

Dengue-2 and yellow fever 17DD viruses infect human dendritic cells, resulting in an induction of activation markers, cytokines and chemokines and secretion of different TNF-α and IFN-α profiles

“…The YF17DD vaccine virus infects cells at inoculum doses equivalent to those used for DENV2 (16681 strain) but showed reduced expression of viral antigens within DCs at all time points tested when compared to DENV. Similar results were described for the YF vaccine strain 204, which is poorly infectious compared with DENV (Deauvieau et al 2007). Other authors used higher MOIs for DENV to obtain the same relative infection level as West Nile virus because these viruses replicate at different rates.…”

“…In our in vitro infection model, we observed markedly higher TNF-α production after infection with pathogenic virus (DENV2) as compared to the non-pathogenic viruses (YF17DD and YF17D/DENV2), providing further evidence that this cytokine plays a role in flavivirus immunopathogenesis. Other authors have also observed TNF-α production in DC or monocyte cultures in the presence of DENV2 and some authors even associate it with the infected cell (Hacker et al 1998, Querec et al 2006, Deauvieau et al 2007, Reis et al 2007, Ahmad et al 2008, Nightingale et al 2008, Levy et al 2009. A moderate level of TNF-α production may be beneficial to mature cells that may become good antigen presenters.…”

“…A moderate level of TNF-α production may be beneficial to mature cells that may become good antigen presenters. This cytokine was detected in YF vaccinated individuals (Roers et al 1994, Querec et al 2006, Deauvieau et al 2007, Levy et al 2009, Silva et al 2011.…”

“…Indeed, these viruses stimulate IFN-α production (Libraty et al 2001, Deauvieau et al 2007, Palmer et al 2007, Querec et al 2009), although IFN-α induction was not compared between viruses in previous reports. Earlier studies show that DENV is able to escape IFN action by inhibiting steps of IFN type I activation pathways through a decrease in the signal transducer and activator of transcription-2 expression (STAT-2) (Jones et al 2005).…”

“…DENV chimeric viruses, earlier reports showed that activation molecules, such as CD80, CD86 and CD83, can be upregulated after DC infection (Libraty et al 2001, Deauvieau et al 2007, Sun et al 2009). Co-stimulation molecules, such as CD38, are present in circulating monocytes but are poorly expressed after their differentiation into immature DCs.…”