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Plasmodium-induced disruption of brain endothelial barrier integrity in vitro and in mice is prevented by inhibitors of farnesyltransferase.

Overview

Authors: Cláudia Gomes1, Kelly A. Crotty1, Mariana C. Borges Silva1, Marilyn Vasquez1, Lizeth Chicas1, Isaac Salzano1, Ana Rodriguez1
  1. Department of Microbiology, New York University Grossman School of Medicine,New York, NY USA
Institutions: New York University (United States)
Journal: Malaria journal, volume 25, issue 1, article 323
Dates: received 25 February 2026; accepted 2 June 2026; published online 23 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s12936-026-05981-2 · PMID 42337625 · PMCID PMC13551684 · OpenAlex W7165681679
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), cellular / molecular (subfield)
Methods: Statistics
Keywords: Cerebral malaria, Blood–brain barrier, Plasmodium falciparum, Plasmodium berghei, Endothelial barrier integrity, Isoprenoids, Farnesyl PYROPHOSPHATE, Farnesyltransferase, Geranylgeranyltransferase, Tipifarnib
MeSH: Blood-Brain Barrier*, Endothelial Cells*, Enzyme Inhibitors*, Farnesyltranstransferase*, Malaria, Cerebral*, Malaria, Falciparum*, Plasmodium falciparum*, Animals, Antimalarials, Brain, Cells, Cultured, Disease Models, Animal, Erythrocytes, Female, Humans, Mice, Plasmodium berghei, Polyisoprenyl Phosphates, Quinolones, Sesquiterpenes (* major topic)
Topic: Malaria Research and Control (Public Health, Environmental and Occupational Health, Medicine), according to OpenAlex
Funding: NIH (R01AI181219)
Citations: not cited yet (Europe PMC); 34 references in the paper

Abstract

Background: Cerebral malaria is a complication of Plasmodium falciparum infections where the integrity of the blood–brain barrier (BBB) is compromised, frequently leading to persistent neurological sequelae or death. The current treatment for cerebral malaria is based on rapid elimination of the parasite with intravenous anti-malarial drugs, but there is no adjunctive treatment that could address the loss of BBB integrity, potentially decreasing sequelae and improving the survival rate. Prenylation, a cellular process that incorporates isoprenoid lipids to specific protein sites, is known to regulate endothelial barrier integrity. Here we have studied the role of the isoprenoid farnesyl pyrophosphate (farnesyl-PP) and of different inhibitors of the enzymes that perform prenylation in endothelial cells to determine their effect on the endothelial barrier disruption induced by Plasmodium falciparum.

Methods: An in vitro model using human brain microvascular endothelial cells (HBMECs) incubated with lysates of P. falciparum-infected red blood cells (iRBCs) and a mouse model of cerebral malaria were used to study the role of the two main prenylation enzymes, farnesyltransferase and geranylgeranyltransferase, in the regulation of endothelial barrier integrity in relation to cerebral malaria.

Results: Addition of exogenous farnesyl-PP to HBMECs incubated with P. falciparum-iRBCs resulted in increased endothelial barrier disruption. Conversely, treatment with inhibitors of farnesyltransferase, but not of geranylgeranyltransferase, resulted in protection of barrier integrity against disruption induced by P. falciparum-iRBCs. Mice infected with Plasmodium berghei that were treated with the farnesyltransferase inhibitor tipifarnib presented delayed onset of cerebral malaria and higher survival rates.

Conclusions: Inhibitors of farnesyltransferase protect human endothelial cell barrier integrity from disruption induced by P. falciparum in vitro and decrease mortality in mice with experimental cerebral malaria, indicating a role for farnesylation in the regulation of barrier integrity during cerebral malaria and identifying a potential drug target for the protection of the endothelium during severe malaria.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Availability of data and materials

All data generated are included in this published article. The dataset analyzed during the current study is available in the Gene Expression Omnibus (GEO) database, accession no. [GSE211439] (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE211439) [9].

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 10 keywords, 20 MeSH terms, 1 funder, 32 references.

Cite

This paper

Gomes, C., Crotty, K. A., Borges Silva, M. C., Vasquez, M., Chicas, L., Salzano, I., & Rodriguez, A. (2026). Plasmodium-induced disruption of brain endothelial barrier integrity in vitro and in mice is prevented by inhibitors of farnesyltransferase. Malaria journal, 25(1), 323. https://doi.org/10.1186/s12936-026-05981-2

BibTeX

@article{gomes2026plasmodium,
author = {Gomes, Cláudia and Crotty, Kelly A. and Borges Silva, Mariana C. and Vasquez, Marilyn and Chicas, Lizeth and Salzano, Isaac and Rodriguez, Ana},
title = {{Plasmodium-induced disruption of brain endothelial barrier integrity in vitro and in mice is prevented by inhibitors of farnesyltransferase}},
journal = {Malaria journal},
year = {2026},
month = jun,
volume = {25},
number = {1},
pages = {323},
publisher = {BMC},
issn = {1475-2875},
doi = {10.1186/s12936-026-05981-2},
url = {https://doi.org/10.1186/s12936-026-05981-2},
pmid = {42337625},
pmcid = {PMC13551684}
}

RIS

TY - JOUR
AU - Gomes, Cláudia
AU - Crotty, Kelly A.
AU - Borges Silva, Mariana C.
AU - Vasquez, Marilyn
AU - Chicas, Lizeth
AU - Salzano, Isaac
AU - Rodriguez, Ana
TI - Plasmodium-induced disruption of brain endothelial barrier integrity in vitro and in mice is prevented by inhibitors of farnesyltransferase
T2 - Malaria journal
J2 - Malar J
PY - 2026
DA - 2026/06/23
VL - 25
IS - 1
SP - 323
SN - 1475-2875
PB - BMC
DO - 10.1186/s12936-026-05981-2
UR - https://doi.org/10.1186/s12936-026-05981-2
LA - en
ER -

CSL-JSON

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