EFFECT OF PYRIDINYL IMIDAZOLE INHIBITORS OF P38 MAP KINASE ON EBOLA REPLICATION AND CYTOKINE INDUCTION IN HUMAN DENDRITIC CELLS
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Date
2015-05
Department
Hood College Biology
Program
Biomedical and Environmental Science
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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.