Ebola viruses (EBOVs) cause highly lethal hemorrhagic disease in humans. One hallmark of fatal EBOV infection in both humans and non-human primates is the early production of copious amounts of pro-inflammatory cytokines. Despite this """"""""pro-inflammatory response,"""""""" fatal cases are typically characterized by little inflammation and a paucity of detectable antibody. EBOV-induced immune suppression is poorly understood, but two recent reports found that EBOVs productively infect human dendritic cells and impair their function. It is possible that suppression of DC function by EBOV may contribute to the impaired immune responses seen in EBOV-infected individuals. However, the mechanism(s) by which EBOV may alter dendritic cell (DC) function remain to be elucidated. My laboratory has demonstrated that expression of the EBOV VP35 protein blocks activation of the host cell IFN system by preventing the phosphorylation and activation of interferon regulatory factor 3 (IRF-3). Additional data demonstrates that VP35 blocks the activation of IRF-3 not only by virus infection but also when activation is induced by expression of adaptor molecules tied to toll-like receptor (TLR) signaling pathways. Given the importance of IFN-related signals and the TLR signaling pathways to the induction of DC maturation by virus infection, the """"""""lFN-antagonist"""""""" function of VP35 may contribute to the EBOV-mediated suppression of DC function. Recent data also indicates that EBOV infection is facilitated by interaction of the EBOV glycoprotein (GP) with the cell surface lectin DC-SlGN. We hypothesize that the """"""""iFN-antagonist"""""""" activity of VP35 and the interaction of GP with DC-SIGN contribute to EBOV-induced immune suppression.
Our specific aims are to: 1. Define the ability of VP35 to block TLR-related signaling pathways. 2. Determine how the """"""""lFN-antagonism"""""""" of VP35 affects human dendritic cell maturation and function. 3. Assess the ability of GP and sGP to modulate human dendritic cell function.
Showing the most recent 10 out of 105 publications
