# Kruppel-Like Factor 2 Counters Vascular and Immunologic Dysfunction in Child Cerebral Malaria

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $576,496

## Abstract

Plasmodium falciparum (Pf) infected erythrocytes can activate endothelial and other myeloid
cells, culminating in systemic inflammation and vascular dysfunction that underlie the
pathogenesis of cerebral malaria. A subset of the polymorphic Pf Erythrocyte Membrane Protein
1 (PfEMP1) family, a virulence protein exported from the intracellular parasite to the infected
erythrocyte surface, is overrepresented in persons with cerebral malaria, who also have
elevated levels of circulating immune complexes that can modify endothelial and monocyte
function. Members of the Kruppel-like family of factors (KLF) are nodal regulators of endothelial
and immune cell function. KLF2 confers an anti-inflammatory, anti-thrombotic, and anti-
permeable phenotype to endothelial and myeloid cells by a common mechanism centered on
inhibition of NFκB, a key transcriptional inducer of pro-inflammatory activation. However, a
causal link between malaria pathogenesis and KLF2 regulation, brain endothelial cell and
monocyte function, and malaria elicited immune complexes has not been established. Our
central hypothesis is that regulation of KLF2 levels in endothelial and myeloid cells is critical for
the pathogenesis of vascular and monocyte dysfunction in cerebral malaria, and that this
myeloid cell dysfunction results from interactions with infected erythrocytes expressing specific
PfEMP1s and Pf elicited immune complexes. To test this hypothesis, we will enroll Kenyan
children presenting with cerebral and uncomplicated malaria and follow them for 6 months. We
will examine 1) the impact of PfEMP1 and patient parasite isolates on endothelial KLF2 and
NFκB expression, 2) patient monocyte phenotype, function, KLF2 expression, and in vitro
monocyte function impacted by PfEMP1 and patient parasite isolates, and 3) the role of immune
complexes in vascular endothelial and monocyte dysfunction isolated from children with
cerebral and uncomplicated malaria. Research proposed here will inform the rational
development of adjunct therapies aimed at reducing vascular dysfunction, mortality and long-
term clinical sequela of cerebral malaria by enhancing endogenous cytoprotective pathways of
endothelial/myeloid lineage cells.

## Key facts

- **NIH application ID:** 9848486
- **Project number:** 5R01AI130131-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** James Walter Kazura
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $576,496
- **Award type:** 5
- **Project period:** 2017-02-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9848486

## Citation

> US National Institutes of Health, RePORTER application 9848486, Kruppel-Like Factor 2 Counters Vascular and Immunologic Dysfunction in Child Cerebral Malaria (5R01AI130131-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9848486. Licensed CC0.

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