B- and T-Cell Responses in Group A Streptococcus M-Protein- or Peptide-Induced Experimental Carditis

Gorton, Davina; Govan, Brenda; Olive, Colleen; Ketheesan, Natkunam

doi:10.1128/iai.01514-08

Cited by 47 publications

(62 citation statements)

References 32 publications

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“…rM5 protein, derived from GAS serotype M5, was cloned and purified as described previously (21). Briefly, extracellular domain of GAS M5 protein (amino acid residues 1 to 450) was amplified by PCR from genomic DNA (strain M5T5/B/PS) using standard techniques.…”

Section: Methodsmentioning

confidence: 99%

“…M protein specific T cell lines were found to home to the valve and induce VCAM-1 expression in a passive T cell transfer model (20). Lymbury and colleagues demonstrated further that epitopes of the GAS M protein also resided in the C repeat region as C repeat epitopes induced inflammatory lesions in the valve of the Lewis rat (21, 22). It is notable that the GAS M5 protein sequences which are associated with heart lesions appear to be different from sequences which are protective epitopes from the N-terminal or C-repeat regions of GAS M proteins which protect against GAS infection and have been utilized in the GAS vaccines (3, 23–25).…”

Section: Introductionmentioning

confidence: 97%

“…Although our earlier studies established that immunization of Lewis rats with GAS M5 or M6 protein (17) or M5 peptides from GAS M5 protein triggered the development of primarily valvulitis which is histologically and immunologically similar to RF/RHD (21), the sequence of events by which this process is initiated and exacerbates remains unclear. One hypothesis has been that repeated streptococcal infections would incite greater immune responses against the heart and induce RF/RHD.…”

Section: Introductionmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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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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“…Furthermore, vaccination with recombinant M protein with potent adjuvants can induce rheumatic carditis in rats (45), and vaccination with a crude preparation may have been responsible for induction of rheumatic fever in children (38). Efforts were therefore made to identify minimal B cell epitope streptococcal vaccines (46).…”

Section: Discussionmentioning

confidence: 99%

Combinatorial Synthetic Peptide Vaccine Strategy Protects against Hypervirulent CovR/S Mutant Streptococci

Pandey

Mortensen

Calcutt

et al. 2016

The Journal of Immunology

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Cluster of virulence responder/sensor (CovR/S) mutant group A streptococci (GAS) are serious human pathogens of multiple M protein strains that upregulate expression of virulence factors, including the IL-8 protease Streptococcus pyogenes cell envelope proteinase (SpyCEP), thus blunting neutrophil-mediated killing and enabling ingress of bacteria from a superficial wound to deep tissue. We previously showed that a combination vaccine incorporating J8-DT (conserved peptide vaccine from the M protein) and a recombinant SpyCEP fragment protects against CovR/S mutants. To enhance the vaccine’s safety profile, we identified a minimal epitope (S2) that was the target for anti-SpyCEP Abs that could protect IL-8 from SpyCEP-mediated proteolysis. Abs from healthy humans and from mice experimentally infected with GAS also recognized S2, albeit at low titers. Native SpyCEP may be poorly immunogenic (cryptic or subdominant), and it would be to the organism’s advantage if the host did not induce a strong Ab response against it. However, S2 conjugated to diphtheria toxoid is highly immunogenic and induces Abs that recognize and neutralize SpyCEP. Hence, we describe a two-component peptide vaccine that induces Abs (anti-S2) that protect IL-8 from proteolysis and other Abs (anti-J8) that cause strain-independent killing in the presence of neutrophils. We show that either component alone is ineffectual in preventing skin infection and bacteremia due to CovR/S mutants but that the combination induces complete protection. This protection correlated with a significant influx of neutrophils to the infection site. The data strongly suggest that the lack of natural immunity to hypervirulent GAS strains in humans could be rectified by this combination vaccine.

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“…The present study aimed to elucidate the role served by Bmi1 and BRG1 in cardiac stem cells following RHD. (20). After the initial dose the rats were carefully monitored and provided with a protein rich pellet form of commercial diet.…”

Section: Introductionmentioning

confidence: 99%

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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B- and T-Cell Responses in Group A Streptococcus M-Protein- or Peptide-Induced Experimental Carditis

Abstract: The etiology of rheumatic fever and rheumatic heart disease (RF/RHD) is believed to be autoimmune, involving immune responses initiated between streptococcal and host tissue proteins through a molecular mimicry mechanism(s) .

Cited by 47 publications

References 32 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

Combinatorial Synthetic Peptide Vaccine Strategy Protects against Hypervirulent CovR/S Mutant Streptococci

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

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