# Mitigation of erythrocyte adhesion in human malaria

> **NIH NIH R21** · TUFTS UNIVERSITY BOSTON · 2024 · $247,500

## Abstract

Abstract
 Malaria is one of the world’s most common and deadly infectious diseases. Approximately 627,000 people, mostly
African children, die each year due to complications of malaria (WHO estimate for 2021). A unique feature of
Plasmodium falciparum malaria is the adhesion of parasite-infected erythrocytes (iRBCs) to vascular endothelium.
Sequestration iRBCs correlates with the sequela of cerebral malaria, a devastating and often fatal consequence of the
disease. The iRBCs develop specialized surface protrusions called knobs mediating their attachment to blood vessels in
multiple organs. Formation of knobs on the surface of iRBCs mediates cytoadherence to endothelial cells. A critical
component of knobs is knob-associated histidine rich protein (KAHRP) that anchors multiple host and parasite derived
proteins to the RBC cytoskeleton. We have identified specific segments of KAHRP that mediate its self-assembly into
spiral-shaped structures by sequential participation of head-to-tail interactions. Domain mapping revealed that the amino
terminal histidine-rich segment of KAHRP functions as a critical determinant of self-assembly. Reconstitution of the
recombinant histidine-rich segment of KAHRP in knobby iRBCs disrupted the knob morphology and abrogated adhesion
of iRBCs in vitro. These results suggest a novel mechanism for disrupting the self-association of KAHRP as a potential
strategy against cytoadhesion in malaria. Guided by these preliminary data, we propose to test the hypothesis that
disrupting specific interactions within KAHRP inhibits knob formation, thus blocking the adhesion of iRBCs to
endothelial cells. This hypothesis will be tested as follows: Aim 1: Mechanism of KAHRP self-assembly and knob
formation. Our results demonstrate that KAHRP self-assembly is mediated through interactions between its histidine rich
region and the C-terminal 5’ repeats. We have identified a specific KAHRP polypeptide that attenuated cytoadherence of
iRBCs as effectively as the KAHRP gene knockdown studies. Moreover, using phage display cDNA technology, we
identified novel KAHRP-binding peptides as potential inhibitors of the knob self-assembly process. We propose to use
erythrocyte loading of KAHRP segments as well as cell permeable peptides to quantify the formation, composition, and
dispersion of knobs using established biochemical and microscopy approaches. Aim 2: Disruption of RBC knob-
endothelial interactions. Using existing recombinant KAHRP segments and newly identified peptides by the phage
display screens, we will evaluate the disruption of iRBCs adhesion to a variety of substrates including endothelial cells,
platelets, and purified receptors. State-of-the-art imaging tools will be used to monitor real time kinetics of cytoadherence
ex vivo. Together, these studies will elucidate the mechanism of knob assembly in the Plasmodium falciparum infected
RBCs and reveal new therapeutic approaches for mitigating the adhesion of infected human RBCs to e...

## Key facts

- **NIH application ID:** 10999601
- **Project number:** 1R21AI186378-01
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Athar H. Chishti
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $247,500
- **Award type:** 1
- **Project period:** 2024-07-09 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999601

## Citation

> US National Institutes of Health, RePORTER application 10999601, Mitigation of erythrocyte adhesion in human malaria (1R21AI186378-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10999601. Licensed CC0.

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