# Molecular Mechanisms in Pediatric Cerebral Malaria Pathogenesis and Immunity

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $719,727

## Abstract

PROJECT ABSTRACT
The human malaria parasite Plasmodium falciparum remains one of the most important causes of childhood
mortality in the world. Cerebral malaria, the most severe complication of P. falciparum infection, is caused by
the sequestration of infected red blood cells in cerebral microvasculature. The var gene or P. falciparum
erythrocyte membrane protein 1 (PfEMP1) is the major cytoadhesion ligand for the parasite. While progress
has been made in understanding the structure and function of PfEMP1 proteins, the key parasite ligand-
receptor interactions involved in cerebral binding remain unestablished. Our recent studies have shown that
specific parasite adhesion types are increased in the blood of cerebral malaria patients, and that parasite
adhesion to endothelial protein C receptor (EPCR) may impair a key anticoagulant and barrier protective
pathway. Moreover, we have shown that hyperlactemia increases fatality risk in pediatric cerebral malaria.
However, large knowledge gaps remain in parasite sequestration in brain, in large part due to its inaccessibility
and the lack of appropriate in vitro models. We have recently developed an innovative technology using 3D
human brain microvessels that recapitulates physiological flow characteristics in health and disease. We are
able to fabricate 3D microvessels with different geometries and lumen dimensions, which allow us to study
parasite adhesion across a range of flow velocities in a single device, as well as to investigate factors that
contribute to microvascular obstruction in malaria. In this project, we will use 3D human brain microvessels in
combination with parasite isolates from pediatric cerebral malaria cases to investigate parasite tropism for
brain, to identify the precise steps of infected red blood cell capture and firm adhesion on brain endothelial
cells, to characterize potential interactions between lactemia and parasite adhesiveness, and to investigate
antibody protective mechanisms in cerebral malaria. The proposed studies will advance our understanding of
the molecular mechanisms of P. falciparum binding in cerebral malaria and immune mechanisms in anti-
disease immunity.

## Key facts

- **NIH application ID:** 9985728
- **Project number:** 5R01AI141602-02
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** JOSEPH DOUGLAS SMITH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $719,727
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985728

## Citation

> US National Institutes of Health, RePORTER application 9985728, Molecular Mechanisms in Pediatric Cerebral Malaria Pathogenesis and Immunity (5R01AI141602-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9985728. Licensed CC0.

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