title: Investigating proteasome inhibitors as potential adjunct therapies for experimental cerebral malaria.
abstract: Aside from antimalarials, there is currently no treatment for cerebral malaria, a fulminant neurological complication of P. falciparum infection that is a leading cause of death in African children. In the mouse model of cerebral malaria, cross-presentation of parasite antigens by brain endothelial cells is thought to be a crucial late step in pathogenesis. We have investigated three proteasome inhibitors as potential adjunct therapies: bortezomib, carfilzomib and ONX-0914. Only carfilzomib, an irreversible inhibitor of both constitutive proteasomes and immunoproteasomes, was able to inhibit cross-presentation of malaria antigen by murine brain endothelial cells in vitro. To mimic the clinical setting, carfilzomib was co-administered with artesunate only when infected mice exhibited neurological defects. However, there was no improvement in survival compared to artesunate monotherapy. The treatment failure was explained by the inability of daily or twice daily bolus doses of carfilzomib to inhibit cross-presentation by brain endothelial cells in vivo. We also report here that bortezomib, which has been associated with neurological adverse events, accelerated death in ECM-infected mice. Future investigations of proteasome inhibitors for modulating cross-presentation during malaria infection should focus on sustained and targeted delivery to brain endothelial cells.
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: S W
authors.identifier: http://orcid.org/0000-0003-4794-1564
authors.initials: SW
authors.lastname: Howland
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore.|Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: G X P
authors.initials: GX
authors.lastname: Ng
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore.|School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: S K
authors.initials: SK
authors.lastname: Chia
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore.|Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: L
authors.initials: L
authors.lastname: Rénia
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D000962:Antimalarials / Q000627:therapeutic use*; D000069286:Bortezomib / Q000627:therapeutic use*; D001921:Brain / Q000469:parasitology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D066298:In Vitro Techniques; D016779:Malaria, Cerebral / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000627:therapeutic use*; D010962:Plasmodium berghei / Q000502:physiology*; D061988:Proteasome Inhibitors / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; D009842:Oligopeptides; C542291:PR-957; D061988:Proteasome Inhibitors; D000069286:Bortezomib; C524865:carfilzomib
keywords: brain; cerebral malaria; cross-presentation; malaria; proteasome inhibitor