Abstract
Fatal Ebola virus infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP) is involved in this process through activating dendritic cells (DCs) and macrophages. However, the mechanism is unclear. Here, we showed that LSECtin (also known as CLEC4G) plays an important role in GP-mediated inflammatory responses in human DCs. Anti-LSECtin mAb engagement induced TNF-α and IL-6 production in DCs, whereas silencing of LSECtin abrogated this effect. Intriguingly, as a pathogen-derived ligand, Ebola GP could trigger TNF-α and IL-6 release by DCs through LSECtin. Mechanistic investigations revealed that LSECtin initiated signaling via association with a 12-kDa DNAX-activating protein (DAP12) and induced Syk activation. Mutation of key tyrosines in the DAP12 immunoreceptor tyrosine-based activation motif abrogated LSECtin-mediated signaling. Furthermore, Syk inhibitors significantly reduced the GP-triggered cytokine production in DCs. Therefore, our results demonstrate that LSECtin is required for the GP-induced inflammatory response, providing new insights into the EBOV-mediated inflammatory response.
Highlights
Ebola virus (EBOV), a member of the family Filoviridae, is the causative agent of severe hemorrhagic fever in humans, which is responsible for the outbreak in West African countries in 2014 [1]
Ebola glycoprotein (GP) is thought to contribute to disease pathogenesis, as high amounts of shed GP from virus-infected cells are detected in patients, and activate macrophages and dendritic cells (DCs) to produce proinflammatory cytokines
We found that after LSECtin “knockdown”, monocyte-derived DCs (MDDCs) stimulated with Ebola virus-like particles (eVLPs) produced less tumor necrosis factor (TNF)-α, IL-6, IL-8, IL-10 and MIP-1α (Fig 1B)
Summary
Ebola virus (EBOV), a member of the family Filoviridae, is the causative agent of severe hemorrhagic fever in humans, which is responsible for the outbreak in West African countries in 2014 [1]. The pre-GP is cleaved by furin into two subunits, GP1 and GP2, which remain linked by a disulfide bond [10,11] This heterodimer (GP1,2) is known to form a trimer on the viral surface. It has been demonstrated that shed GP can induce the production of proinflammatory cytokines by activating noninfected DCs and macrophages, which can explain the dysregulated inflammatory host reactions to Ebola infection [13]. Ebola virus-like particles (eVLPs) consisting of virus protein (VP40) and GP are able to induce the activation of DCs [14]. GP is required for eVLPs to induce DCs cytokine production [15,16] All of these results support that GP can induce inflammatory response. The molecular mechanism underlying GP-mediated inflammatory responses is unclear
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