Genetic Approaches and Therapeutic Strategies Against Severe Malaria

Doctoral Dissertation
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Abstract

Malaria parasites induce uncomplicated and severe malaria such as anemia, cerebral malaria and death in a wide range of mammalian hosts. In recent years, our lab has used combination of rodents and rodent malaria parasite Plasmodium berghei ANKA (PbA) to understand the role of parasite proteins in severe malaria. In this project, we investigated the role of members of merozoite surface protein 7 (MSP7) family for their modulatory effect on malaria invasion, death and cerebral malaria using in-vivo rodent models in acute infection BALB/c mouse and experimental cerebral malaria (ECM) C57BL/6 mouse. This is the first report that shows that MSP7 related proteins 1 and 2 (MSRP1 and MSRP2) enhance normocyte invasion and contribute to death during acute infection. In addition, this study strongly supports MSP7 and related proteins (MSRP1 & MSRP2) as virulent factors in the manifestation of ECM.

Cerebral malaria (CM) is a major complication of Plasmodium falciparum infection with high mortality and morbidity in endemic regions. Presently there are not many effective treatments to manage the severe pathologies associated with CM and thus we are interested in testing and validating new therapeutics for the treatment of this neurological disorder. We carried out in-vivo experiments in the ECM mouse model to evaluate the efficacy of three small molecules for the treatment of CM. The first molecule, 2-hydroxypropyl-beta-cyclodextrin, (HPβCD) is a form of cyclodextrin, a cyclic oligosaccharide composed of α-(1,4) linked glucopyranose subunits that acts as both a drug delivery vehicle and a therapeutic agent. The second molecule, ND-364 compound, is a matrix metalloprotease 9 (MMP9) inhibitor and also a potent gelatinase inhibitor. However, we also evaluated in-vivo efficacy of a liposomal formulation of synthetically modified artesunate. While our in-vivo studies with both HPβCD and ND-364 showed no significant therapeutic benefits, the liposomal artesunate formulation exhibited an outstanding efficacy in both early and late stage murine CM models. Treatment with liposomal artesunate formulation resulted in complete cure of blood infection, abrogation of death and prevention of neurocognitive impairment in the late stage ECM. This formulation is thus proposed as a future treatment option for late stage cerebral malaria.

Attributes

Attribute NameValues
URN
  • etd-10012014-213644

Author Aanuoluwa Adeola Adelani
Advisor Kasturi Haldar
Contributor Shaun Lee, Committee Member
Contributor Jeffrey Schorey, Committee Member
Contributor Kasturi Haldar, Committee Chair
Contributor Michael Ferdig, Committee Member
Degree Level Doctoral Dissertation
Degree Discipline Biological Sciences
Degree Name PhD
Defense Date
  • 2014-07-30

Submission Date 2014-10-01
Country
  • United States of America

Subject
  • Severe malaria

  • Rodent models

  • Cerebral malaria

  • Malaria therapy

  • Merozoite surface protein

  • Plasmodium species

Publisher
  • University of Notre Dame

Language
  • English

Record Visibility Public
Content License
  • All rights reserved

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