Immunopathogenesis of falciparum malaria: implications for adjunctive therapy in the management of severe and cerebral malaria

Abstract

Despite optimal antimalarial treatment and advances in malaria eradication, the mortality rate associated with severe malaria due to Plasmodium falciparum infection, including cerebral malaria (CM), remains unacceptably high. This suggests that strategies directed solely at parasite eradication may be insufficient to prevent neurological complications and death in all cases of CM. Therefore, there is an urgent need to develop innovative adjunctive therapeutic strategies to effectively reduce CM-associated mortality. CM pathogenesis is believed to be due, in part, to an aberrant host immune response to P. falciparum, resulting in deleterious consequences, including vascular activation and dysfunction. Development of effective and affordable therapeutic strategies that act to modulate the underlying host-mediated immunopathology should be explored to improve outcome. In this article, we summarize immunomodulatory therapies that have been assessed in clinical trials to date, and highlight novel and promising treatment strategies currently being investigated to address this major global health challenge.

Keywords::

• endothelium
• host response
• immunomodulatory therapy
• inflammation
• L-arginine
• nitric oxide
• Plasmodium falciparum
• PPARγ agonist
• severe/cerebral malaria
• theranostics

Acknowledgement

The authors would like to thank Dr Karlee Silver and the anonymous peer reviewers for their expert insight and critical evaluation of this manuscript.

Financial & competing interests disclosure

This study was supported, in part, by the Canadian Institutes of Health Research CIHR MOP-115160 and MOP-13721 (Kevin C Kain), CIHR Canada Research Chairs (Kevin C Kain, W Conrad Liles), and Defense Advanced Research Projects Agency (DARPA; Kevin C Kain, W Conrad Liles). Sarah J Higgins is generously funded by a CIHR Frederick Banting and Charles Best Canada Graduate Scholarship. Kevin C Kain and W Conrad Liles are listed as inventors on a patent owned by the University Health Network related to host biomarkers of malaria. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.