Evidence for two distinct classes of streptococcal M protein and their relationship to rheumatic fever.

Abstract

Group A streptococci are human pathogens that infect primarily at the skin or nasopharyngeal mucosa . A major virulence factor present on the streptococcal surface is M protein, a molecule of which there exists more than 80 distinct serological types. M protein provides the streptococcus with the ability to resist phagocytosis by polymorphonuclear leukocytes, and only antibodies directed to type-specific determinants permit opsonophagocytosis in whole blood (1, 2). Structural studies reveal that M protein is composed of two a-helical polypeptide chains that give rise to a coiled-coil, fibrillar structure extending -60 nm from the cell surface (3, 4). The antigenically variable determinants of type specificity are located in the NH2-terminal portion of the molecule, distal to the cell wall (2, 5). Some epitopes of the Mprotein molecule are shared among different M serotypes, and the degree ofrelatedness increases at sites closer to the COOH terminus (6, 7).Recent progress towards a group A streptococcal vaccine indicates that mucosal immunization with shared immunodeterminants of M protein leads to reduced pharyngeal colonization in a mouse model (8). To better define those epitopes for potential use in a non-type-specific-based vaccine, we sought to gain a more detailed understanding of the antigenic relatedness of surface-exposed portions of M protein among isolates of the same serotype, and between isolates of distinct serotypes. In this report, we describe an antigenically conserved domain within the surface-exposed portion of M protein of certain serological types, and provide evidence for two distinct classes of M protein molecules based on the presence or absence of this antigenic domain.Acute rheumatic fever (ARF)' is one complication that can follow a nasopharyngeal streptococcal infection, and epidemiological studies point to a strong association between streptococci ofcertain serological M types and ARF attacks (9). Defining a particular serotype as "rheumatogenic" is not entirely clearcut since pharyngitis generally precedes the onset of ARF by 3-4 wk and thus, there is uncertainty as to whether the streptococcus isolated at the time of an ARF attack is of the same lineage as that which caused pharyngitis. Nevertheless, it is apparent that streptococci

Temporal Association of the Appearance of Mucoid Strains ofStreptococcus PyogenesWith a Continuing High Incidence of Rheumatic Fever in Utah

“…The demonstration that those strains that primarily cause pharyngitis and RF (class 1) have a different M-protein molecular structure from those strains that primarily cause skin infections and glomerulonephritis (class 2) supports the concept of rheumatogenic strains. 24 Our recent experience offers additional support that a limited number of M types are rheumatogenic and often are mucoid. Although M-18 was dominant, it was not the exclusive M type that was mucoid in the community.…”

Identification of a divergent M protein gene and an M protein-related gene family in Streptococcus pyogenes serotype 49

“…Preliminary evidence suggests that this putative lineage may represent the OF-positive serotypes. The conserved repeated regions of these two categories of M proteins are clearly different as determined by antibody-binding studies (4). In addition, DNA probes from various conserved regions within and surrounding OF-negative M protein genes bind much more strongly to chromosomal DNAs from other OF-negative serotypes than they do to DNAs from OFpositive serotypes (E. Haanes-Fritz, Ph.D. thesis, University of Minnesota, Minneapolis, 1989; E. Haanes, D. Heath, and P. P. Cleary, submitted for publication).…”

“…For example, the OF-positive strains are predominantly isolated from skin infections, as opposed to throat infections (37). Furthermore, Bessen et al recently demonstrated that antibodies directed against defined epitopes in the conserved domain of M6 bound to surface epitopes of OF-negative but not OF-positive strains (4). Detailed studies of M proteins from OF-positive strains have been hampered, however, by the fact that these M proteins tend to be less immunogenic than their OF-negative counterparts (53).…”

The M protein of group A Streptococcus is a key virulence factor and a clinically relevant strain identification marker

“…The tendency to induce acute rheumatic fever is possibly the best-studied example. [9][10][11] Other determinants of virulence are encoded by a variety of chromosomal genes, many of which are associated with highly mobile phage elements. For these, the genetic links to virulence are far less clear and likely polygenic.…”