title: Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells.
abstract: Antigen presenting cells (APCs), including macrophages and dendritic cells, are early and sustained targets of Ebola virus (EBOV) infection in vivo. Because EBOV activates mitogen-activated protein kinase (MAPK) signaling upon infection of APCs, we evaluated the effect of pyridinyl imidazole inhibitors of p38 MAPK on EBOV infection of human APCs and EBOV mediated cytokine production from human DCs. The p38 MAPK inhibitors reduced viral replication in PMA-differentiated macrophage-like human THP-1 cells with an IC50 of 4.73μM (SB202190), 8.26μM (p38kinhIII) and 8.21μM (SB203580) and primary human monocyte-derived dendritic cells (MDDCs) with an IC50 of 2.67μM (SB202190). Furthermore, cytokine production from EBOV-treated MDDCs was inhibited in a dose-dependent manner. A control pyridinyl imidazole compound failed to inhibit either EBOV infection or cytokine induction. Using an established EBOV virus-like particle (VLP) entry assay, we demonstrate that inhibitor pretreatment blocked VLP entry suggesting that the inhibitors blocked infection and replication at least in part by blocking EBOV entry. Taken together, our results indicate that pyridinyl imidazole p38 MAPK inhibitors may serve as leads for the development of therapeutics to treat EBOV infection.
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Ft. Detrick, MD 21702, United States.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Johnson
authors.affiliation: Dept. of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Martinez
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Ft. Detrick, MD 21702, United States.
authors.forename: Anna N
authors.initials: AN
authors.lastname: Honko
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Ft. Detrick, MD 21702, United States.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hensley
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Ft. Detrick, MD 21702, United States.
authors.forename: Gene G
authors.initials: GG
authors.lastname: Olinger
authors.affiliation: Dept. of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: chris.basler@mssm.edu.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors*; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology*; D029043:Ebolavirus / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D053586:Virus Internalization / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Antigen-presenting cell; Dendritic cell; Ebola virus; Entry; THP-1; p38 MAPK