Inhibition of RhoA Prevents Cryptococcus Neoformans Capsule Glucuronoxylomannan-Stimulated Brain Endothelial Barrier Disruption

Overview

Journal J Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2024 Apr 16

PMID 38622836

Authors

Melissa E Munzen

Cristian Mathew

Vanessa Enriquez

Amanjeet Minhas

Claudia L Charles-Nino

Durvinand Saytoo

Marta Reguera-Gomez

Michael R Dores

Luis R Martinez

Affiliations

Soon will be listed here.

Abstract

Cryptococcus neoformans (Cn) is an opportunistic fungus that causes severe central nervous system (CNS) disease in immunocompromised individuals. Brain parenchyma invasion requires fungal traversal of the blood-brain barrier. In this study, we describe that Cn alters the brain endothelium by activating small GTPase RhoA, causing reorganization of the actin cytoskeleton and tight junction modulation to regulate endothelial barrier permeability. We confirm that the main fungal capsule polysaccharide glucuronoxylomannan is responsible for these alterations. We reveal a therapeutic benefit of RhoA inhibition by CCG-1423 in vivo. RhoA inhibition prolonged survival and reduced fungal burden in a murine model of disseminated cryptococcosis, supporting the therapeutic potential of targeting RhoA in the context of cryptococcal infection. We examine the complex virulence of Cn in establishing CNS disease, describing cellular components of the brain endothelium that may serve as molecular targets for future antifungal therapies to alleviate the burden of life-threatening cryptococcal CNS infection.

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