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

Author:

Munzen Melissa E1,Mathew Cristian2,Enriquez Vanessa1,Minhas Amanjeet2,Charles-Niño Claudia L1,Saytoo Durvinand2,Reguera-Gomez Marta1,Dores Michael R2,Martinez Luis R1345ORCID

Affiliation:

1. Department of Oral Biology, University of Florida College of Dentistry , Gainesville

2. Department of Biology, Hofstra University , Hempstead, New York

3. Emerging Pathogens Institute, University of Florida , Gainesville

4. Center for Immunology and Transplantation, University of Florida , Gainesville

5. Center for Translational Research in Neurodegenerative Disease, University of Florida , Gainesville

Abstract

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.

Funder

National Institute of Allergy and Infectious Diseases

US National Institutes of Health

University of Florida College of Dentistry’s Comprehensive Training Program in Oral Biology

Publisher

Oxford University Press (OUP)

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3