Review
Molecular basis of group A streptococcal virulence

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Summary

The group A streptococcus (GAS) (Streptococcus pyogenes) is among the most common and versatile of human pathogens. It is responsible for a wide spectrum of human diseases, ranging from trivial to lethal. The advent of modern techniques of molecular biology has taught much about the organism's virulence, and the genomes of several GAS types have now been deciphered. Surface structures of GAS including a family of M proteins, the hyaluronic acid capsule, and fibronectin-binding proteins, allow the organism to adhere to, colonise, and invade human skin and mucus membranes under varying environmental conditions. M protein binds to complement control factors and other host proteins to prevent activation of the alternate complement pathway and thus evade phagocytosis and killing by polymorphonuclear leucocytes. Extracellular toxins, including superantigenic streptococal pyrogenic exotoxins, contribute to tissue invasion and initiate the cytokine storm felt responsible for illnesses such as necrotising fasciitis and the highly lethal streptococcal toxic shock syndrome. Progress has been made in understanding the molecular epidemiology of acute rheumatic fever but less is understood about its basic pathogenesis. The improved understanding of GAS genetic regulation, structure, and function has opened exciting possibilities for developing safe and effective GAS vaccines. Studies directed towards achieving this long-sought goal are being aggressively pursued.

Section snippets

M protein

The major human host defence against invasive GAS infection is that of phagocytosis and killing by polymorphonuclear leucocytes (PML). Thus, a critical somatic GAS virulence factor is an antiphagocytic surface constituent known as M protein.

The structural basis of the biological properties of M protein has been elucidated over the past three decades.2, 3 M protein is composed of two polypeptide chains complexed in an alpha-helical coiled-coil configuration anchored in the cell membrane,

The streptococcal genome

In little over a year the complete genome sequences from three S pyogenes types, M1,109 M3,110 and M18,111 have been reported. GAS serotypes may be associated with distinct clinical syndromes, with M1 and M3 frequently isolated from cases of necrotising fasciitis and STSS, and M18 strains associated with the epidemic of acute rheumatic fever seen in the Salt Lake City area since the mid 1980s. This genome information provides insight into the subtle genetic differences between streptococcal

Genetic regulation of streptococcal virulence factors

Control of the expression of the described virulence factors over time and under diverse environmental circumstances depends on a complex system of genetic modulation. Of the known transcriptional regulators in GAS, the two most intensively studied are Mga113 (multiple gene regulator), the regulator of M protein expression, and a two-component regulatory system known as CsrRS114 (capsule synthesis regulator) or alternatively, CovRS115 (“control of virulence genes”), which represses the

Acute rheumatic fever

The development of acute rheumatic fever (ARF) requires antecedent infection with a specific organism, the GAS, at a specific body site, the upper respiratory tract. Although the exact mechanism by which GAS induces the disease remains unexplained, most attention has been focused on the notion of autoimmunity, or, more precisely, molecular mimicry. This theory is rendered more credible by several examples of antigenic similarity between somatic constituents of GAS and human tissues, including

Acute glomerulonephritis

Acute poststreptococcal glomerulonephritis (APSGN) follows infection with a limited number of GAS serotypes. Type 12 is the most frequent M serotype causing APSGN after pharyngitis or tonsillitis, whereas M-49 is the type most frequently related to pyoderma-associated nephritis. Not all streptococcal strains belonging to these serotypes are nephritogenic, however. There are no reliable biological markers to differentiate nephritogenic from nonnephritogenic streptococci. APSGN is almost always

Prospects for a group A streptococcal vaccine

The persistence of rheumatic fever in many developing countries of the world, the apparent increase in life-threatening invasive GAS infections in North America and Europe, and the revolution in molecular biology have spurred attempts to achieve a long-sought goal: a safe and effective vaccine against the GAS. The most promising approaches are M protein-based and include multivalent type-specific vaccines146, 147 and those directed at non-type specific, highly conserved portions of the molecule.

Search strategy and selection criteria

In preparing this paper we reviewed articles in the Medline database for “Streptococcus pyogenes”, with special attention to “pathogenesis”, “genetics”, and “virulence”. In addition, we reviewed the bibliographies of previously published articles and reviews relating to the topics discussed herein. Papers included in the review were selected for scientific quality and relevance to the topic.

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