EFFECT OF PYRIDINYL IMIDAZOLE INHIBITORS OF P38 MAP KINASE ON EBOLA REPLICATION AND CYTOKINE INDUCTION IN HUMAN DENDRITIC CELLS

Abstract

Antigen presenting cells, 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 antigen presenting cells, the effect of pyridinyl imidazole inhibitors of p38 MAPK on EBOV entry, infection and cytokine production from these cells was explored. The p38 MAPK inhibitors reduced viral replication in PMA-differentiated THP-1 cells with an IC50 of 4.73µM (SB 202190), 8.26µM (p38kinhIII) and 8.21µM (SB 203580) and primary human monocyte derived dendritic cells (MDDCs) with an IC50 of 2.67µM (SB 202190). Furthermore, cytokine and chemokine production from EBOV-treated MDDCs was inhibited in a dose-dependent manner. Using an established EBOV virus-like particle (VLP) entry assay, inhibitor pretreatment blocked VLP entry, suggesting that the inhibitors blocked infection and replication at least in part by blocking EBOV entry. Taken together, these results indicate that pyridinyl imidazole p38 MAPK inhibitors may serve as candidates for the development of therapeutics to treat EBOV infection.