Ebola and Marburg virus-like particles activate human myeloid dendritic cells

Abstract

The filoviruses, Ebola (EBOV) and Marburg (MARV), are potential global health threats, which cause deadly hemorrhagic fevers. Although both EBOV and MARV logarithmically replicate in dendritic cells (DCs), these viruses do not elicit DC cytokine secretion and fail to activate and mature infected DCs. Here, we employed virus-like particles (VLPs) of EBOV and MARV to investigate whether these genome-free particles maintain similar immune evasive properties as authentic filoviruses. Confocal microscopy indicated that human myeloid-derived DCs readily took up VLPs. However, unlike EBOV and MARV, VLPs induced maturation of DCs including upregulation of costimulatory molecules (CD40, CD80, CD86), major histocompatibility complex (MHC) class I and II surface antigens, and the late DC maturation marker CD83. The chemokine receptors CCR5 and CCR7 were also modulated on VLP-stimulated DCs, indicating that DC could migrate following VLP exposure. Furthermore, VLPs also elicited DC secretion of the pro-inflammatory cytokines TNF-alpha, IL-8, IL-6, and MIP-1alpha. Most significantly, in stark contrast to DC treated with intact EBOV or MARV, DC stimulated with EBOV or MARV VLPs showed enhanced ability to support human T-cell proliferation in an allogenic mixed lymphocyte response (MLR). Thus, our findings suggest that unlike EBOV and MARV, VLPs are effective stimulators of DCs and have potential in enhancing innate and adaptive immune responses.

Development and characterization of Rift Valley fever virus-like particles

“…Furthermore, VLPs are able to undergo efficient antigen processing and presentation through either major histocompatibility complex class I or class II molecules, thereby inducing strong humoral and cellular immune responses (Bachmann et al, 1996;Pejawar-Gaddy et al, 2010;Win et al, 2011;Liu et al, 2013). Moreover, VLPs can directly induce dendritic cell maturation, and thus positively regulate costimulatory molecule expression and cytokine secretion, further activating CD8 + T lymphocytes (Bosio et al, 2004;Yang et al, 2004). Three VLP vaccines have thus far been approved for human use: the bivalent human papillomavirus (HPV) vaccine (Cervarix, GlaxoSmithKline, USA), the quadrivalent HPV vaccine (Merck, USA), and the hepatitis B vaccine (Merck) (Kushnir et al, 2012).…”

Active Suppression of the Pulmonary Immune Response by Francisella tularensis Schu4

“…For example, intranasal infection of mice with Bordetella pertussis results in a similar profile of phenotypic, but not functional, maturation of DC (13). Virus-like particles that are morphologically similar to intact virus but lack the components required for replication and assembly readily activate numerous cells, including NK cells and DC (14,15). In contrast to these more attenuated pathogens and preparations, it has been shown that more virulent organisms interfere with multiple aspects of host/DC responses.…”

Status and challenges of filovirus vaccines

“…Co-expression of ZEBOV GP and VP40 in 293T cells resulted in the production of ZEBOV VLPs (eVLPs) that were indistinguishable by electron microscopy from live ZEBOV particles [15,101]. When eVLPs were cultured with mouse bonemarrow-derived dendritic cells, they induced maturation of the cells and production of inflammatory cytokines [102]. eVLPs were immunogenic in mice when give i.m.…”