Sikder, Suchandan (2018) Determination of the role of group G Streptococcus in the pathogenesis of rheumatic heart disease using a rat model. PhD thesis, James Cook University.

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Abstract

Acute rheumatic fever and rheumatic heart disease (ARF/RHD) have long been described as autoimmune sequelae of Streptococcus pyogenes or group A streptococcal (GAS) infection characterised by inflammatory changes to heart, joint, brain, blood vessel and skin tissue. In ARF/RHD both antibody and T-cell responses against immunodominant GAS virulence factors including M-proteins, cross-react with host tissue proteins. The M-protein antibodies activate heart endothelial cells by upregulation of adhesion molecules such as VCAM-1 and ICAM-1 to trigger an inflammatory response. Repeat exposure to GAS perpetuates the autoimmune process leading to permanent cardiac damage. However, in some ARF/RHD endemic regions, throat carriage of GAS is low but carriage of the related Streptococcus dysgalactiae subspecies equisimilis (SDSE), also known as β-haemolytic groups C and G streptococci (GCS/GGS) is high. As SDSE also express M-protein, it has been postulated that streptococci other than GAS may have the potential to initiate or exacerbate ARF/RHD. Further investigation of this hypothesis was limited due to the unavailability of an appropriate experimental model for this uniquely human disease. Using an animal model initially developed to investigate S. pyogenes associated ARF/RHD, we have now discovered that GGS does indeed cause both myocarditis and valvulitis, hallmarks of ARF/RHD.

We injected Lewis rats with whole-killed GGS or GGS M-protein Stg480 with or without whole-killed GAS and GAS rM5 protein to induce carditis. Carditis development was determined by electrocardiographic and echocardiographic examination of rats, and histological examination after heart retrieval. Antibody and T-cell reactivity to M-proteins and antibody cross-reactivity to host cardiac myosin and collagen I has been demonstrated. Remarkably the histological, immunological and functional changes in the hearts of rats exposed to GGS are identical to those exposed to GAS. Furthermore, antibody cross-reactivity to cardiac myosin was comparable in both GGS and GAS exposed animals providing additional evidence that GGS can induce and/or exacerbate ARF/RHD. The results provide further evidence that the heterologous GAS and GGS antigen combinations are equally as effective as homologous antigens at inducing heart pathology, heart conduction and valve abnormalities and potentially autoreactive immune responses.

The role of GAS and GGS M-protein specific antibodies and T-cells in upregulation of VCAM-1 and ICAM-1 has been investigated in vitro using cultured rat aortic endothelial cells, and in vivo in tissue sections taken from Lewis rats immunised with GAS and GGS M-proteins. Upregulation of VCAM-1 and ICAM-1 was observed in an endothelial cell line stimulated with antibodies and/or T-cells, and in heart sections of rats injected with GAS and GGS M-proteins. Using a Transwell cell culture system, we observed that T-cells from M-protein immunised animals migrated through the endothelial monolayer. Furthermore, we observed the development of carditis in Lewis rats following injection of serum and/or splenocytes from rats previously immunised with GAS rM5 protein.

Our findings suggest that group G Streptococcus (GGS) and its M-protein has the potential to induce autoimmune mediated carditis in the Lewis rat model of RHD. The data provides further direct evidence that M-protein specific lymphocytes and antibodies facilitate migration of inflammatory cells to the heart and likely contribute to heart pathology in this animal model as well in human RHD.

Item ID:	56013
Item Type:	Thesis (PhD)
Keywords:	rheumatic heart disease; rheumatic fever; group G Streptococcus; autoimmunity; Streptococcus; murine model
Related URLs:	https://researchonline.jcu.edu.au/37654/
Copyright Information:	Copyright © 2018 Suchandan Sikder
Additional Information:	Publications arising from this thesis are available from the Related URLs field. The publications are: Rush, Catherine M., Govan, Brenda L., Sikder, Suchandan, Williams, Natasha L., and Ketheesan, Natkunam (2014) Animal models to investigate the pathogenesis of rheumatic heart disease. Frontiers in Pediatrics, 2. pp. 1-6.
Date Deposited:	02 Nov 2018 02:00
FoR Codes:	11 MEDICAL AND HEALTH SCIENCES > 1108 Medical Microbiology > 110801 Medical Bacteriology @ 100%
SEO Codes:	92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 50% 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 50%
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