Date of Award

Spring 5-15-2017

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Human malaria is caused by five species of Plasmodium. Of these, P. falciparum is the deadliest and is the only species that causes cerebral malaria (CM). CM is a disease of the vascular endothelium characterized by parasite sequestration, increased inflammatory cytokine production, vascular leakage and leukocyte infiltration. A distinguishing feature of P. falciparum infection is the parasite’s production and secretion of histidine-rich protein II (HRPII). HRPII accumulates to high concentrations (up to 100 µg/ml) in serum, which correlates with disease severity. Due to high serum levels of this protein, HRPII has classically been considered a biomarker for P. falciparum infection. Although many functions have been ascribed to HRPII, the function of this protein remains ambiguous. Our work provides a new framework for thinking of this protein from serum biomarker to parasite virulence factor. Using a cellular model of the blood-brain barrier, we demonstrate that HRPII activates the innate immune system in human cerebral microvascular endothelial cells, resulting in redistribution of tight junction proteins and compromise of barrier integrity. This process is Myd88-dependent, NFĸB-mediated and requires inflammasome activation. Intravenous infusion of HRPII induced vascular leakage in the cerebellum and cortex of mice and increased early mortality in a P. berghei ANKA experimental cerebral malaria model. Analogously, transgenic P. berghei expressing falciparum HRPII produced more severe disease than wild-type or control P. berghei. HRPII induced endothelial expression of adhesion receptors used by plasmodium parasites, suggesting that this protein also contributes to pathogenesis by enhancing parasite cytoadherence and thereby avoiding splenic destruction. This study establishes that HRPII is a Plasmodium falciparum virulence factor that triggers an innate immune inflammatory response in vascular endothelium and contributes to cerebral malaria by compromising the integrity of the blood-brain barrier.

Language

English (en)

Chair and Committee

Daniel E. Goldberg

Committee Members

Robyn Klein, Michael Diamond, David Sibley, Niraj Tolia,

Comments

Permanent URL: https://doi.org/10.7936/K7J38QZH

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