Interaction between Ebola virus glycoprotein and host toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1.
Ebola virus initially targets monocytes and macrophages, which can lead to the release of proinflammatory cytokines and chemokines. These inflammatory cytokines are thought to contribute to the development of circulatory shock seen in fatal Ebola virus infections. Here we report that host Toll-like receptor 4 (TLR4) is a sensor for Ebola virus glycoprotein (GP) on virus-like particles (VLPs) and that resultant TLR4 signaling pathways lead to the production of proinflammatory cytokines and suppressor of cytokine signaling 1 (SOCS1) in a human monocytic cell line and in HEK293-TLR4/MD2 cells stably expressing the TLR4/MD2 complex. Ebola virus GP was found to interact with TLR4 by immunoprecipitation/Western blot analyses, and Ebola virus GP on VLPs was able to stimulate expression of NF-kappaB in a TLR4-dependent manner. Interestingly, we found that budding of Ebola virus VLPs was more pronounced in TLR4-stimulated cells than in unstimulated control cells. In sum, these findings identify the host innate immune protein TLR4 as a sensor for Ebola virus GP which may play an important role in the immunopathogenesis of Ebola virus infection.
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Atsushi
A
Okumura
Paula M
PM
Pitha
Akihiko
A
Yoshimura
Ronald N
RN
Harty
D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D029043:Ebolavirus / Q000737:chemistry* / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D009000:Monocytes; D016328:NF-kappa B / Q000096:biosynthesis; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology*; D014771:Virion / Q000737:chemistry
D016207:Cytokines; D006023:Glycoproteins; D016328:NF-kappa B; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014764:Viral Proteins