Rift valley fever virus infection of human cells and insect hosts is promoted by protein kinase C epsilon.
As an arthropod-borne human pathogen, Rift Valley fever virus (RVFV) cycles between an insect vector and mammalian hosts. Little is known about the cellular requirements for infection in either host. Here we developed a tissue culture model for RVFV infection of human and insect cells that is amenable to high-throughput screening. Using this approach we screened a library of 1280 small molecules with pharmacologically defined activities and identified 59 drugs that inhibited RVFV infection with 15 inhibiting RVFV replication in both human and insect cells. Amongst the 15 inhibitors that blocked infection in both hosts was a subset that inhibits protein kinase C. Further studies found that infection is dependent upon the novel protein kinase C isozyme epsilon (PKCε) in both human and insect cells as well as in adult flies. Altogether, these data show that inhibition of cellular factors required for early steps in the infection cycle including PKCε can block RVFV infection, and may represent a starting point for the development of anti-RVFV therapeutics.
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Claire Marie
CM
Filone
Sheri L
SL
Hanna
M Cecilia
MC
Caino
Shelly
S
Bambina
Robert W
RW
Doms
Sara
S
Cherry
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004175:Diptera / Q000235:genetics / Q000378:metabolism / Q000821:virology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007313:Insecta / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012296:Rift Valley fever virus / Q000187:drug effects / Q000502:physiology*; D014709:Vero Cells
D000098:Acetophenones; D053119:Benzophenanthridines; D001578:Benzopyrans; D004791:Enzyme Inhibitors; C085746:rottlerin; C016299:chelerythrine; D051744:Protein Kinase C-epsilon