Tropical acute rheumatic fever and associatedstreptococcal infections compared with concurrent acute glomerulonephritis

Potter, Elizabeth V.; Svartman, Mauri; Mohammed, Isahak; Cox, Reginald; Poon-King, Theo; Earle, David P.

doi:10.1016/s0022-3476(78)80036-5

Cited by 67 publications

(24 citation statements)

References 38 publications

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“…Despite the high level of genetic diversity among GAS, many strains share key ecological properties. The rich epidemiological history of GAS disease reveals that superficial infection of the throat (pharyngitis) versus skin (impetigo) is largely caused by strains having discrete sets of M or emm types (2,14,16,18,21,34,47,52,67). This study sought to gain insight on the genetic basis for the two ecological phenotypes associated with primary GAS infections, using a population genomics approach.…”

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confidence: 99%

Whole-Genome Association Study on Tissue Tropism Phenotypes in Group A Streptococcus

et al. 2011

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Group A Streptococcus (GAS) has a rich evolutionary history of horizontal transfer among its core genes. Yet, despite extensive genetic mixing, GAS strains have discrete ecological phenotypes. To further our understanding of the molecular basis for ecological phenotypes, comparative genomic hybridization of a set of 97 diverse strains to a GAS pangenome microarray was undertaken, and the association of accessory genes with emm genotypes that define tissue tropisms for infection was determined. Of the 22 nonprophage accessory gene regions (AGRs) identified, only 3 account for all statistically significant linkage disequilibrium among strains having the genotypic biomarkers for throat versus skin infection specialists. Networked evolution and population structure analyses of loci representing each of the AGRs reveal that most strains with the skin specialist and generalist biomarkers form discrete clusters, whereas strains with the throat specialist biomarker are highly diverse. To identify coinherited and coselected accessory genes, the strength of genetic associations was determined for all possible pairwise combinations of accessory genes among the 97 GAS strains. Accessory genes showing very strong associations provide the basis for an evolutionary model, which reveals that a major transition between many throat and skin specialist haplotypes correlates with the gain or loss of genes encoding fibronectin-binding proteins. This study employs a novel synthesis of tools to help delineate the major genetic changes associated with key adaptive shifts in an extensively recombined bacterial species.

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Whole-Genome Association Study on Tissue Tropism Phenotypes in Group A Streptococcus

et al. 2011

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“…Numerous epidemiological studies report differences in the strains of S. pyogenes recovered from oropharyngeal infection (pharyngitis) versus superficial skin infection (impetigo) (4,13,15,16,18,34,43,49,65). Markers used to identify distinct strains were often based on antigenic forms of the M surface protein (M serotypes).…”

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Population Genetics and Linkage Analysis of Loci within the FCT Region ofStreptococcus pyogenes

et al. 2007

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The FCT regions of Streptococcus pyogenes strains encode a variety of cell wall-anchored surface proteins that bind the extracellular matrix of the human host and/or give rise to pilus-like appendages. Strong linkage is evident between transcription-regulatory loci positioned within the FCT and emm regions and the emm pattern genotype marker for preferred infection of the throat or skin. These findings provide a basis for the hypothesis that FCT region gene products contribute to tissue-specific infection. In an initial series of steps to address this possibility, the FCT regions of 13 strains underwent comparative sequence analysis, the gene content of the FCT region was characterized for 113 strains via PCR, and genetic linkage was assessed. A history of extensive recombination within FCT regions was evident. The emm pattern D-defined skin specialist strains were highly homogenous in their FCT region gene contents, whereas the emm pattern A-C-defined throat specialist strains displayed a greater variety of forms. Most pattern A-C strains harbored prtF1 (75%) but lacked cpa (75%). In contrast, the majority of emm pattern D strains had cpa (92%) but lacked prtF1 (79%). Models based on FCT and emm region genotypes revealed the most parsimonious pathways of evolution. Using niche-determining candidate genes to infer phylogeny, emm pattern E strains-the so-called generalists, which lack a strong tissue site preference-occupied a transition zone separating most throat specialists from skin specialists. Overall, population genetic analysis supports the possibility that the FCT region gives rise to surface proteins that are largely necessary, but not always sufficient, to confer tissue site preference for infection.

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“…Variability in the N-terminal of M proteins generated more than 100 distinct M serotypes. Rheumatogenicity of Streptococcus pyogenes strains, which are also referred to as group A streptococci (GAS), was found to correlate with certain M serotypes in different parts of the world (12)(13)(14), indicating that such M proteins may be directly involved in the pathogenesis of ARF/RHD. Different autoimmune mechanisms have been proposed for pathogenesis of ARF (3,8,15) that bases on M proteins and other surface components of GAS as causative agents and results in autoimmune response against host proteins of cardiac tissues (3,4,8,(15)(16)(17).…”

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Identification of a Streptococcal Octapeptide Motif Involved in Acute Rheumatic Fever

Dinkla

Nitsche-Schmitz

Barroso

et al. 2007

Journal of Biological Chemistry

115

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Acute rheumatic fever is a serious autoimmune sequela of pharyngitis caused by certain group A streptococci. One mechanism applied by streptococcal strains capable of causing acute rheumatic fever is formation of an autoantigenic complex with human collagen IV. In some geographic regions with a high incidence of acute rheumatic fever pharyngeal carriage of group C and group G streptococci prevails. Examination of such strains revealed the presence of M-like surface proteins that bind human collagen. Using a peptide array and recombinant proteins with targeted amino acid substitutions, we could demonstrate that formation of collagen complexes during streptococcal infections depends on an octapeptide motif, which is present in collagen binding M and M-like proteins of different ␤-hemolytic streptococcal species. Mice immunized with streptococcal proteins that contain the collagen binding octapeptide motif developed high serum titers of anti-collagen antibodies. In sera of rheumatic fever patients such a collagen autoimmune response was accompanied by specific reactivity against the collagen-binding proteins, linking the observed effect to clinical cases. Taken together, the data demonstrate that the identified octapeptide motif through its action on collagen plays a crucial role in the pathogenesis of rheumatic fever. Eradication of streptococci that express proteins with the collagen binding motif appears advisable for controlling rheumatic fever. Acute rheumatic fever (ARF)3 is one of the most serious diseases caused by streptococci and occurs as an autoimmune sequela of untreated or inadequately treated group A streptococcal pharyngitis (1). ARF and the subsequent rheumatic heart disease (RHD) remain significant causes of cardiovascular disease today (2, 3). The most devastating effects are on children and young adults in their most productive years (2-4). According to a recent estimate more than 15 million people have RHD, more than 0.5 million acquire ARF each year, and about 0.25 million deaths annually are directly attributable to ARF or RHD (2). The fact that penicillin has clearly failed to eradicate ARF and that streptococcal vaccines are still years away from being available underlines the need for novel control strategies (5, 6). Identification of the pathogenic mechanisms underlying ARF is a prerequisite for the development of the necessary diagnostic and preventive approaches.Major virulence factors of streptococci that infect humans are the M and M-like proteins. They exert anti-phagocytic effects (7-10) and facilitate streptococcal survival within polymorph nuclear neutrophils (11). Variability in the N-terminal of M proteins generated more than 100 distinct M serotypes.

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Tropical acute rheumatic fever and associatedstreptococcal infections compared with concurrent acute glomerulonephritis

Cited by 67 publications

References 38 publications

Whole-Genome Association Study on Tissue Tropism Phenotypes in Group A Streptococcus

Whole-Genome Association Study on Tissue Tropism Phenotypes in Group A Streptococcus

Population Genetics and Linkage Analysis of Loci within the FCT Region ofStreptococcus pyogenes

Identification of a Streptococcal Octapeptide Motif Involved in Acute Rheumatic Fever

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