# Pathogenesis of HRPII in Cerebral Malaria

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $381,250

## Abstract

Project Summary/Abstract
Malaria afflicts several hundred million and kills more than 600,000 people each
year, mostly children in Sub-Saharan Africa. Plasmodium falciparum causes
nearly all the malaria deaths. The most dreaded P. falciparum complication,
cerebral malaria, is often fatal despite antimalarial treatment. Cerebral malaria
(CM) is a cerebrovascular disease. Parasitized red blood cells (RBCs) sequester
in the small vessels and can cause microvascular obstruction. While this
mechanical plugging of vessels is thought to contribute to disease, endothelial
dysfunction is proposed to play a major role. Pathologically, redistribution of tight
junction proteins is observed in association with blood-brain barrier leakage.
Nearly a decade ago, it was observed that P. falciparum-infected RBCs placed
on an in vitro endothelial barrier caused increased permeability across the
monolayer. We have discovered that this effect is due to export of the parasite-
produced protein histidine-rich protein II (HRPII). HRPII binds to endothelial cells
and triggers the inflammasome, resulting in endothelium junctional protein
redistribution and barrier disruption. In vivo, HRPII causes increased blood-brain
barrier permeability and leads to increased mortality in murine models of cerebral
malaria. Unanswered questions are: how does HRPII bind to the endothelial
surface? How does HRPII trigger the inflammasome? Can we block the effects of
this toxin pharmacologically?
To address these questions, aim 1 will identify endothelial HRPII receptor and
inflammasome initiation mechanism. Both candidate gene and unbiased
approaches will be tried. Aim 2 will focus on identification of therapeutic
strategies for amelioration of cerebral malaria. We will test existing drugs against
the inflammasome pathway as well as endothelial barrier-stabilizing drugs, using
our mouse assays for HRPII action. We anticipate that the proposed studies will
yield great insight into the pathogenesis of cerebral malaria and will point the way
to new therapies to mitigate the devastating complications of falciparum malaria
infections.

## Key facts

- **NIH application ID:** 9913445
- **Project number:** 5R01AI126909-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Daniel E. Goldberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2016-05-12 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913445

## Citation

> US National Institutes of Health, RePORTER application 9913445, Pathogenesis of HRPII in Cerebral Malaria (5R01AI126909-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9913445. Licensed CC0.

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