title: Effective adjunctive therapy by an innate defense regulatory peptide in a preclinical model of severe malaria.
abstract: Case fatality rates for severe malaria remain high even in the best clinical settings because antimalarial drugs act against the parasite without alleviating life-threatening inflammation. We assessed the potential for host-directed therapy of severe malaria of a new class of anti-inflammatory drugs, the innate defense regulator (IDR) peptides, based on host defense peptides. The Plasmodium berghei ANKA model of experimental cerebral malaria was adapted to use as a preclinical screen by combining late-stage intervention in established infections with advanced bioinformatic analysis of early transcriptional changes in co-regulated gene sets. Coadministration of IDR-1018 with standard first-line antimalarials increased survival of infected mice while down-regulating key inflammatory networks associated with fatality. Thus, IDR peptides provided host-directed adjunctive therapy for severe disease in combination with antimalarial treatment.
authors.affiliation: Walter and Eliza Hall Institute for Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Ariel H
authors.initials: AH
authors.lastname: Achtman
authors.forename: Sandra
authors.initials: S
authors.lastname: Pilat
authors.forename: Charity W
authors.initials: CW
authors.lastname: Law
authors.forename: David J
authors.initials: DJ
authors.lastname: Lynn
authors.forename: Laure
authors.initials: L
authors.lastname: Janot
authors.forename: Matt L
authors.initials: ML
authors.lastname: Mayer
authors.forename: Shuhua
authors.initials: S
authors.lastname: Ma
authors.forename: Jason
authors.initials: J
authors.lastname: Kindrachuk
authors.forename: B Brett
authors.initials: BB
authors.lastname: Finlay
authors.forename: Fiona S L
authors.initials: FS
authors.lastname: Brinkman
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
authors.forename: Louis
authors.initials: L
authors.lastname: Schofield
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000627:therapeutic use*; D002478:Cells, Cultured; D005260:Female; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000187:drug effects / Q000472:pathogenicity
chemical_list: D000962:Antimalarials; D023181:Antimicrobial Cationic Peptides; C555052:innate defense regulating peptide 1018