Animal Models to Investigate the Pathogenesis of Rheumatic Heart Disease

Rush, Catherine M.; Govan, Brenda; Sikder, Suchandan; Williams, Natasha L.; Ketheesan, Natkunam

doi:10.3389/fped.2014.00116

Cited by 25 publications

(22 citation statements)

References 28 publications

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“…The RAV model is the only credible model currently in use to dissect the multiple mechanisms that may play a role in the immunopathogenesis of RF/RHD (47). Currently using this model we aimed to determine whether repeated exposure to different GAS M serotypes, both ‘rheumatogenic’ and ‘non-rheumatogenic’ or non-group A streptococci, are sufficient to exacerbate rheumatic carditis with symptomatology.…”

Section: Discussionmentioning

confidence: 99%

Repeat exposure to group A streptococcal M protein exacerbates cardiac damage in a rat model of rheumatic heart disease

et al. 2016

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Rheumatic fever and rheumatic heart disease (RF/RHD) develop following repeated infection with group A streptococci (GAS). We used the Rat Autoimmune Valvulitis (RAV) model of RF/RHD to demonstrate that repetitive booster immunization with GAS-derived recombinant M protein (rM5) resulted in an enhanced anti-cardiac myosin antibody response that may contribute to the breaking of immune tolerance leading to RF/RHD and increased infiltration of heart valves by mononuclear cells. With each boost, more inflammatory cells were observed infiltrating heart tissue which could lead to severe cardiac damage. We also found evidence that both complement and anti-M protein antibodies in serum from rM5-immunized rats have the potential to contribute to inflammation in heart valves by activating cardiac endothelium. More importantly we have demonstrated by electrocardiography for the first time in the RAV model that elongation of P-R interval follows repetitive boost with rM5. Our observations provide experimental evidence for cardiac alterations following repeat exposure to GAS M protein with immunological and electrophysiological features resembling that seen in humans following recurrent GAS infection.

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Section: Discussionmentioning

confidence: 99%

Repeat exposure to group A streptococcal M protein exacerbates cardiac damage in a rat model of rheumatic heart disease

et al. 2016

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“…A rat model was previously developed to mimic rheumatic heart disease. [22][23][24][25][26] Histological examination of cardiac tissue in rats immunised with recombinant M5 (rM5) revealed the presence of inflammatory lesions in both the myocardium and valve tissue 22 which were akin to the histological changes observed in RF/RHD in humans. In this investigation the rat Figure 3.…”

Section: Vaccine Formulation Does Not Induce Pathology In a Lewis Ratmentioning

confidence: 99%

“…The rats were immunized as described previously. 18,22,26 Briefly, 8-week-old female Lewis rats (n D 5/group) were immunized subcutaneously on day 0 into the hock with either rM5 (500 ug), J8-DT (150 ug) or DT (150 ug) emulsified 1:1 with Complete Freund's Adjuvant (Sigma, Australia) in a total volume of 200 ul following anesthesia with isofluorane (5%) in 100% oxygen. On day 1 and 3, the rats received an intraperitoneal injection of 1 £ 10 10 whole killed Bordetella pertussis cells as an additional adjuvant.…”

Section: Vaccine Formulation Does Not Induce Pathology In a Lewis Ratmentioning

confidence: 99%

Preclinical immunogenicity and safety of a Group A streptococcal M protein-based vaccine candidate

Batzloff

Fåne

Gorton

et al. 2016

Human Vaccines & Immunotherapeutics

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Streptococcus pyogenes (group A streptococcus, GAS) causes a wide range of clinical manifestations ranging from mild self-limiting pyoderma to invasive diseases such as sepsis. Also of concern are the post-infectious immune-mediated diseases including rheumatic heart disease. The development of a vaccine against GAS would have a large health impact on populations at risk of these diseases. However, there is a lack of suitable models for the safety evaluation of vaccines with respect to post-infectious complications. We have utilized the Lewis Rat model for cardiac valvulitis to evaluate the safety of the J8-DT vaccine formulation in parallel with a rabbit toxicology study. These studies demonstrated that the vaccine did not induce abnormal pathology. We also show that in mice the vaccine is highly immunogenic but that 3 doses are required to induce protection from a GAS skin challenge even though 2 doses are sufficient to induce a high antibody titer.

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“…However, the role served by Bmi1 and BRG1 in cardiac stem cells remains unclear. It is difficult to create animal models of RHD and studying the different pathological stages of RHD remains a challenge (30). In the present study, an animal model of RHD that mimicked the pathological characteristics observed in humans with RHD was successfully developed.…”

Section: Discussionmentioning

confidence: 98%

Bmi1 and BRG1 drive myocardial repair by regulating cardiac stem cell function in acute rheumatic heart disease

Xiao

Zhang

Tao

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Rheumatic heart disease (RHD) occurs due to the accumulation of complications associated with rheumatic fever, and it results in high morbidity and mortality. The majority of cases of RHD are diagnosed in the chronic stages, when treatment options are limited. A small reservoir of cardiac stem cells is responsible for maintaining cardiac homeostasis and repairing tissue damage. Understanding the role of cardiac stem cells and the various proteins responsible for their functions in different pathological stages of RHD is an important area of investigation. Polycomb complex protein BMI-1 (Bmi1) and transcription activator BRG1 (BRG1) are associated with the maintenance of stemness in various types of stem cells. The present study investigated the role served by Bmi1 and BRG1 in cardiac stem cells during various pathological stages of RHD through immunohistochemistry and western blotting. A rat model of RHD was established via immunization with the Group A Streptococcus M5 protein.The rat was demonstrated to develop acute RHD 2 months after the final immunization, characterized by cardiac inflammation and tissue damage. Chronic RHD was identified 4 months after the final immunization, revealed by cardiac tissue compression and shrinkage. Expression of the cardiac stem cell marker mast/stem cell growth factor receptor kit was identified to be elevated during acute RHD, but downregulated in the chronic stages of RHD. A similar pattern of expression was revealed for Bmi1 and BRG1, indicating that they serve a role in regulating cardiac stem cell proliferation during acute RHD. These results suggest that cardiac stem cells serve a supportive role in the acute, but not chronic, stages of RHD via expression of Bmi1 and BRG1. IntroductionRheumatic heart disease (RHD) is a major health issue worldwide, which primarily results in cardiovascular disease and associated morbidities (1,2). RHD most frequently affects children between 5 and 14 years old (3). The diagnosis of RHD has gradually increased, particularly in the latent stage of the disease (4,5). A previous pathological study demonstrated that valvular inflammation occurs as the disease progresses, which is due to the presence of immunodominant epitopes following infection (6). There are numerous limitations including the asymptomatic nature of the disease and a lack of trained practitioners for screening RHD in the latent stage of the disease (7). In certain cases of chronic RHD, valve replacement is the only treatment option (8). The formation of rheumatic lesions and Aschoff bodies are indicative of the active form of RHD (9-11).Cardiac stem cells have the ability to convert fibrotic scars, which are formed through injury or inflammation, into nascent cardiomyocytes (12). Cardiomyocytes have a low turnover, which reflects the small reservoir of cardiac stem cells (13). The underlying molecular mechanisms of the self-renewal, potency and survival abilities of cardiac stem cells remain unclear and require further study (14). A number of biomarkers are used ...

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Animal Models to Investigate the Pathogenesis of Rheumatic Heart Disease

Cited by 25 publications

References 28 publications

Repeat exposure to group A streptococcal M protein exacerbates cardiac damage in a rat model of rheumatic heart disease

Repeat exposure to group A streptococcal M protein exacerbates cardiac damage in a rat model of rheumatic heart disease

Preclinical immunogenicity and safety of a Group A streptococcal M protein-based vaccine candidate

Bmi1 and BRG1 drive myocardial repair by regulating cardiac stem cell function in acute rheumatic heart disease

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