Abstract
The pathogenesis of Acute Rheumatic Fever/Rheumatic Heart Disease (ARF/RHD) and associated neurobehavioral complications including Sydenham's chorea (SC) is complex. Disease complications triggered by Group A streptococcal (GAS) infection are confined to human and determining the early events leading to pathology requires a robust animal model that reflects the hallmark features of the disease. However, modeling these conditions in a laboratory animal, of a uniquely human disease is challenging. Animal models including cattle, sheep, pig, dog, cat, guinea pigs rats and mice have been used extensively to dissect molecular mechanisms of the autoimmune inflammatory responses in ARF/RHD. Despite the characteristic limitations of some animal models, several rodent models have significantly contributed to better understanding of the fundamental mechanisms underpinning features of ARF/RHD. In the Lewis rat autoimmune valvulitis model the development of myocarditis and valvulitis with the infiltration of mononuclear cells along with generation of antibodies that cross-react with cardiac tissue proteins following exposure to GAS antigens were found to be similar to ARF/RHD. We have recently shown that Lewis rats injected with recombinant GAS antigens simultaneously developed cardiac and neurobehavioral changes. Since ARF/RHD is multifactorial in origin, an animal model which exhibit the characteristics of several of the cardinal diagnostic criteria observed in ARF/RHD, would be advantageous to determine the early immune responses to facilitate biomarker discovery as well as provide a suitable model to evaluate treatment options, safety and efficacy of vaccine candidates. This review focuses on some of the common small animals and their advantages and limitations.
Highlights
The concept of comparative medicine developed based on the theory that animal species share physiological, anatomical and behavioral characteristics similar to human [1]
In a credible animal model symptoms of physiological, anatomical and behavioral conditions must be comparable to those observed in human disease
Sex and age difference affects the development of autoimmune complication; selection of an appropriate animal model is important to investigate the pathogenesis of Acute Rheumatic Fever/Rheumatic Heart Disease (ARF/Rheumatic Heart Disease (RHD)) and associated complications
Summary
The concept of comparative medicine developed based on the theory that animal species share physiological, anatomical and behavioral characteristics similar to human [1]. Rabbits, pigs, sheep, goats, cattle, cats, dogs, and non-human primates have been used as experimental model to understand the disease mechanism of ARF/RHD and to investigate the rheumatogenic potential of GAS M proteins [23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Upon injection of GAS antigens, or cardiac myosin, animals developed myocarditis and/or valvulitis similar to patients with ARF/RHD with antibody and T-cell responses that cross-reacted with host cardiac proteins. Studies on Lewis rats indicated the role of infiltrating CD4+ cells and macrophages in the disease process In addition to these histological changes, Lewis rats demonstrated electrocardiographic and echocardiographic changes following exposure to killed GAS and recombinant GAS M proteins induce cardiac functional abnormalities comparable to patients with ARF (Figure 1D) [35, 36]. References [20, 43] [77] [31, 32, 35, 36] [26, 27, 30, 34,35,36] [36] [23, 25] [25] [23,24,25]
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