# Inflammatory Responses Potentiate GAS M Protein Induced Cardiac Damage in an Experimental Model of Rheumatic Heart Disease

## TL;DR

This study shows that inflammatory responses, when combined with a streptococcal protein, worsen heart damage in a rat model of rheumatic heart disease.

## Contribution

The study is the first to demonstrate the role of inflammatory responses in promoting cardiac damage in an animal model of ARF/RHD.

## Key findings

- Bordetella pertussis toxin enhances inflammatory and autoimmune responses leading to cardiac damage in the RAV model.
- A robust Th1/Th17 response is a major driver of cardiac pathology in the RAV model.
- Inflammatory responses are necessary for the progression of ARF/RHD in susceptible individuals.

## Abstract

Acute rheumatic fever (ARF) and Rheumatic heart disease (RHD) are autoimmune sequalae, that develops in a proportion of individuals exposed to group A streptococcal infection. The autoimmune pathology of ARF/RHD is multifactorial. Both host and pathogen‐associated factors including genetic predisposition, inflammatory responses, tissue cross‐reactive antibodies and T‐cells contribute to disease development and progression. Hitherto, the role of inflammatory responses in ARF/RHD has never been demonstrated in animal models. In this study for the first time, using the Rat Autoimmune valvulitis model of RHD, we demonstrate the requirement for inflammatory responses in promoting cardiac damage in ARF/RHD.

To determine the role of inflammatory responses we used Bordetella pertussis toxin (BPTx) as an adjuvant to enhance the inflammatory responses initiated by GAS M protein.

Lewis rats injected with GAS rM5 emulsified in Complete Freund's Adjuvant (CFA) and co‐adjuvant BPTx, had enhanced valvulitis and inflammatory changes as shown by; (a) elevated levels of circulating inflammatory cytokines; (b) functional changes characterized by a prolonged P‐R interval in electrocardiography, (c) enhanced cross‐reactive antibody production against cardiac and connective tissue proteins; and (d) increased infiltration of IFN‐γ+ and IL‐17A+ secreting leukocytes into myocardium and valvular tissues.

These studies have established that in addition to exposure to GAS M protein, BPTx accelerate the inflammatory and autoimmune processes leading to cardiac damage. These observations substantiate the hypothesis that, in susceptible individuals robust inflammatory responses facilitate the progression of ARF/RHD.

Group A streptococcal M protein elicit antibody and T‐cell responses that cross react with cardiac and connective tissue proteins in the Rat Autoimmune Valvulitis (RAV) model of rheumatic heart disease. Bordetella pertussis Toxin induce a robust Th1 response that potentiates the autoimmune process in the RAV model A robust Th1/Th17 response was found to be a major driver of cardiac pathology in the RAV model