Disruption of the blood-brain barrier contributes to neurobehavioral changes observed in rheumatic heart disease

Rukshan Ahamed Mohamed Rafeek; Riya Thapa; Samarjeet Saluja; Bipandeep Banga; David McMillan; Kadaba Sri Sriprakash; Nicholas M Andronicos; Adam Hamlin; Natkunam Ketheesan

doi:10.1002/ame2.70012

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Disruption of the blood-brain barrier contributes to neurobehavioral changes observed in rheumatic heart disease

Journal article

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Disruption of the blood-brain barrier contributes to neurobehavioral changes observed in rheumatic heart disease

Rukshan Ahamed Mohamed Rafeek, Riya Thapa, Samarjeet Saluja, Bipandeep Banga, David McMillan, Kadaba Sri Sriprakash, Nicholas M Andronicos, Adam Hamlin and Natkunam Ketheesan

Animal Models and Experimental Medicine, Vol.8(6), pp.1138-1145

2025

DOI: https://doi.org/10.1002/ame2.70012

PMCID: PMC12204997

PMID: 40059805

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Abstract

Sydenham's chorea

blood–brain‐barrier

group a streptococcus

animal model

rheumatic fever

Sydenham chorea (SC) is the neurological manifestation associated with acute rheumatic fever (ARF). ARF and rheumatic heart disease (RHD) are autoimmune complications triggered by a group A streptococcal (GAS) infection. In ARF/RHD and SC, tissue cross-reactive antibodies and T-cells generated against GAS antigens have been implicated in the pathogenesis. In SC, antibodies against GAS antigens are known to cross-react with neuronal proteins causing neurological manifestations including choreiform movements and neuropsychiatric symptoms such as irritability, attention deficit, and obsessive-compulsive disorder. Previous studies in a rat autoimmune valvulitis (RAV) model of RHD, have shown that injection of streptococcal M protein could cause both cardiac and neurological symptoms. In this study it was shown that adoptive transfer of serum with anti-GAS M antibodies to naive rats caused carditis but failed to demonstrate neurobehavioral symptoms. However, when the blood-brain barrier (BBB) was disrupted using lipopolysaccharide, all animals that received anti-GAS M protein antibodies, developed neurobehavioral defects in addition to carditis. This highlights that impaired BBB integrity is essential for the development of neurobehavioral symptoms. The use of the RAV model and the disruption of BBB required for the development of neurobehavioral changes provides a platform to further investigate the mechanisms that lead to antibodies binding to basal ganglia structures that cause SC.

Details

Title: Disruption of the blood-brain barrier contributes to neurobehavioral changes observed in rheumatic heart disease
Authors: Rukshan Ahamed Mohamed Rafeek (Corresponding Author) - University of New England
Riya Thapa - University of New England
Samarjeet Saluja - University of New England
Bipandeep Banga - University of New England
David McMillan - University of the Sunshine Coast, Queensland, School of Science, Technology and Engineering
Kadaba Sri Sriprakash - University of New England
Nicholas M Andronicos - University of New England
Adam Hamlin (Corresponding Author) - University of New England
Natkunam Ketheesan - University of the Sunshine Coast, Queensland, School of Science, Technology and Engineering
Publication details: Animal Models and Experimental Medicine, Vol.8(6), pp.1138-1145
Publisher: John Wiley & Sons, Inc.
Date published: 2025
DOI: 10.1002/ame2.70012
ISSN: 2576-2095
PMID: 40059805; PMC12204997
Copyright note: © 2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Data Availability: Data available on request from the authors.
Grants: Preclinical evaluation of a streptococcal peptide based specific diagnostic for rheumatic fever and the identification of proteins responsible for the pathogenesis of rheumatic heart disease, 2010336, National Health and Medical Research Council (Australia, Canberra) - NHMRC
Grant note: Destination Australia Program (DAP) scholarships; International Postgraduate Research Award (IPRA) from University of New England; Australian Government Research Training Program (RTP)
Organisation Unit: School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 991110915802621
Output Type: Journal article

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