Bioengineered human microvessel platforms for modeling disease mechanisms and developing adjunctive therapy for cerebral malaria

The National Institute of Allergy and Infectious Diseases awarded $922,799 to Seattle Children's Research Institute on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop bioengineered human brain microvessel platforms for modeling cerebral malaria disease mechanisms and developing adjunctive therapies.

The research addresses the pathogenesis of cerebral malaria caused by Plasmodium falciparum, which leads to sequestration of infected red blood cells in brain microcirculation, resulting in microvascular obstruction, inflammation, endothelial dysfunction, and blood-brain barrier breakdown. Current treatments target only the parasite; no adjunctive therapies exist to mitigate vascular inflammation and endothelial dysfunction. The project will develop three-dimensional bioengineered human brain microvessels to conduct controlled studies of P. falciparum disease mechanisms. Aim 1 will elucidate how adherent infected erythrocytes interact with host pro-inflammatory mediators to promote inflammation and permeability in microvessels and will examine the role of monocytes in inflammatory injury. Aim 2 will apply advanced bioengineered microvessel platforms that mimic the smallest brain blood vessels to understand spatial and temporal changes induced by transient obstruction. The long-term goal is to identify cellular and molecular mechanisms underlying cerebrovascular endothelial dysfunction in cerebral malaria and develop new therapies that reduce mortality and morbidity.

Work is performed in Seattle, Washington, with a period of performance from September 1, 2026, through August 31, 2027. The assistance type is a Project Grant.

Abstract

Cerebral malaria, a severe complication caused by the plasmodium falciparum parasite, is a life-threatening condition that manifests as a coma in infected individuals. The case fatality rate is 15% and many child survivors can have long-term neurocognitive complications. A hallmark of cerebral malaria is the sequestration of p. Falciparum-infected red blood cells in the brain microcirculation, leading to microvascular obstruction, inflammation, endothelial dysfunction, and breakdown of the blood-brain barrier. Current treatments primarily target the parasite, with no adjunctive therapies available to mitigate vascular inflammation and endothelial dysfunction. The long-term goal of this project is to elucidate the cellular and molecular mechanisms underlying cerebrovascular endothelial dysfunction in cerebral malaria and to develop new therapies that decrease mortality and morbidity from this disease. The pathogenesis of cerebral malaria remains incompletely understood, partly due to the lack of animal models that fully replicate the complex human pathology, particularly the sequestration of p. Falciparum-infected erythrocytes in the brain microcirculation. Towards this end, we have developed bioengineered 3D human brain microvessels for controlled studies to delineate p. Falciparum disease mechanisms. In aim 1, we will elucidate how adherent p. Falciparum-infected erythrocytes interact with host pro-inflammatory mediators to promote inflammation and permeability in microvessels and study the role of monocytes in driving inflammatory injury. Microvascular obstruction and brain hemorrhages are hallmarks of fatal cerebral malaria. In aim 2, we will apply advanced bioengineered microvessel platforms that mimic the smallest blood vessels in the brain to understand the spatial and temporal changes induced by transient plugging of microvessels by adherent parasites and how the microvessels respond following flow restoration. To explore therapeutic strategies, we will assess the repurposing of kinase inhibitors to modulate inflammatory injury. In aim 3, we will evaluate kinase inhibitors using dual models: p. Falciparum-infected engineered 3D brain microvessels and the p. Berghei-mouse experimental cerebral malaria model. The proposed work here aims to advance the molecular understanding of endothelial dysfunction in cerebral malaria and inform the development of new adjunctive therapies to mitigate its morbidity and mortality.