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Investigating proteasome inhibitors as potential adjunct therapies for experimental cerebral malaria
Author(s) -
Howland S. W.,
Ng G. X. P.,
Chia S. K.,
Rénia L.
Publication year - 2015
Publication title -
parasite immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.795
H-Index - 75
eISSN - 1365-3024
pISSN - 0141-9838
DOI - 10.1111/pim.12277
Subject(s) - carfilzomib , cerebral malaria , artesunate , bortezomib , immunology , proteasome inhibitor , malaria , plasmodium falciparum , medicine , in vivo , pharmacology , biology , proteasome , antigen presentation , multiple myeloma , immune system , t cell , microbiology and biotechnology
Summary 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.