Antigenic diversity within a family of M proteins from group A streptococci: evidence for the role of frameshift and compensatory mutations

Relf, Wendy A.; Martin, Diana; Sriprakash, Kadaba S.

doi:10.1016/0378-1119(94)90198-8

Cited by 29 publications

(18 citation statements)

References 24 publications

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“…However, it might also be explained by the likelihood that changes in GAS serotype (i.e., emm type) occur by both mutation and recombination, whereas recombination involving the capsular biosynthetic genes is the only known mechanism underlying serotype changes in pneumococci (7). In the presence of strong selective immunological pressures, the diversification of emm genes might be further promoted by highly mutable processes, such as frameshift mutation and DNA slipped-strand mispairing (21,28,31). Unless recombinational exchanges that result in the presence of the same emm type in different lineages have occurred relatively recently, the diversifying selection applied by the host immune system is likely to result in the divergence of the emm types of the parental and recipient lineages.…”

Section: Discussionmentioning

confidence: 99%

Multilocus Sequence Typing ofStreptococcus pyogenesand the Relationships betweenemmType and Clone

et al. 2001

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Multilocus sequence typing (MLST) is a tool that can be used to study the molecular epidemiology and population genetic structure of microorganisms. A MLST scheme was developed for Streptococcus pyogenes and the nucleotide sequences of internal fragments of seven selected housekeeping loci were obtained for 212 isolates. A total of 100 unique combinations of housekeeping alleles (allelic profiles) were identified. The MLST scheme was highly concordant with several other typing methods. The emm type, corresponding to a locus that is subject to host immune selection, was determined for each isolate; of the >150 distinct emm types identified to date, 78 are represented in this report. For a given emm type, the majority of isolates shared five or more of the seven housekeeping alleles. Stable associations between emm type and MLST were documented by comparing isolates obtained decades apart and/or from different continents. For the 33 emm types for which more than one isolate was examined, only five emm types were present on widely divergent backgrounds, differing at four or more of the housekeeping loci. The findings indicate that the majority of emm types examined define clones or clonal complexes. In addition, an MLST database is made accessible to investigators who seek to characterize other isolates of this species via the internet (http://www.mlst.net).Group A streptococci (GAS; Streptococcus pyogenes) are highly prevalent bacterial pathogens, having a worldwide distribution, whereby humans serve as their primary biological host. Most often, GAS infect superficial tissue sites, involving the mucosal epithelium of the upper respiratory tract (URT) or the epidermal layer of the skin, leading to pharyngitis or impetigo, respectively. On rare occasions, a GAS infection can lead to invasive disease that includes cellulitis, bacteremia, necrotizing fasciitis, and toxic shock syndrome, which can be life-threatening conditions. In addition, GAS contribute to morbidity through delayed nonsuppurative sequelae, such as rheumatic fever and acute glomerulonephritis.The M and M-like proteins of GAS form surface fibrils that provide the basis for a widely used serological typing scheme. For many molecules studied in detail, the M serotype (M type) is usually defined by antigenic target sites contained within the distal, amino-terminal ends of these fibrillar proteins, and Ͼ80 distinct M types have been identified. M and M-like proteins are also key virulence factors, and protective immunity against GAS infection is type specific (8, 23). More recently, a genotypic typing scheme based on the emm genes that encode M and M-like proteins has become widely used and Ͼ150 different emm types have been characterized (15; http://www.cdc.gov /ncidod/biotech/strep/strains.html). The antigenic heterogeneity exhibited by this family of proteins reflects the strong impact of host immunity on the generation of diversity within this bacterial species.Numerous other genotypic methods have been developed for the typing of GAS isolates. Vir-ty...

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Section: Discussionmentioning

confidence: 99%

Multilocus Sequence Typing ofStreptococcus pyogenesand the Relationships betweenemmType and Clone

et al. 2001

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“…In principle, single or multiple frameshift mutations could exploit alternative coding registers to change the sequence or recruit modules of sequence into the expressed product (36). Although it is speculative in the Vlp system, indirect evidence for such frameshifts has been reported in a recent survey of streptococcal M proteins (23). Translational frameshifting (17) could also recruit alternative ORFs in vlp genes.…”

Section: Discussionmentioning

confidence: 99%

Increased structural and combinatorial diversity in an extended family of genes encoding Vlp surface proteins of Mycoplasma hyorhinis

et al. 1995

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Variable lipoproteins (Vlp) constitute the major coat protein of Mycoplasma hyorhinis. They are products of multiple, divergent, single-copy genes organized in a chromosomal cluster. Three genes, vlpA, vlpB, and vlpC, have been previously identified in clonal isolates of M. hyorhinis SK76. Each is linked to a characteristic promoter region containing a homopolymeric tract of adenine residues [poly(A) tract], subject to hypermutation, that transcriptionally controls phase variation of vlp genes and leads to combinatorial surface mosaics of distinct Vlp products. The size of the natural vlp gene repertoire is unknown but may critically determine the degree of structural and combinatorial diversity available in this species. In this study, the vlp repertoire of M. hyorhinis GDL-1 was characterized and shown to contain three additional genes, vlpD, vlpE, and vlpF, clustered with other known vlp genes in the order 5-vlpD-vlpE-vlpF-IS-vlpA-IS-vlpB-vlpC-3, where IS represents copies of the IS1221 element of M. hyorhinis. The 5 boundary of this expanded family was identical to that of the more limited family 5-vlpA-IS-vlpB-vlpC-3 previously described in a clonal isolate of strain SK76. A recombinant construct containing vlpD, vlpE, and vlpF expressed antigenically distinguishable products corresponding to each gene. These genes encode characteristic C-terminal repetitive regions that are subject to size variation by insertion or deletion of intragenic repeats but maintain an extended, charged structure. Each vlp gene also contained characteristic alternative open reading frames, which provide a potential reservoir of coding sequence for Vlp diversity, possibly recruited through insertion and/or deletion mutations. These findings demonstrate a vastly expanded potential for structural diversity and combinatorial display of surface mosaics on this organism and suggest that modulation of the vlp repertoire, possibly in conjunction with mobile elements, may determine the capacity for surface variation in natural populations and laboratory strains of this mycoplasma species.The variable lipoprotein (Vlp) system of Mycoplasma hyorhinis provides a mutational strategy for adaptive surface variation that generates extreme population diversity in the major coat proteins expressed on this wall-less procaryote (27,28,38,40). The complexity of this system and its role as a prototype for analogous emerging systems in other mycoplasma species warrants a detailed characterization of the genetic and structural attributes contributing to its adaptive capabilities. Vlps are procaryotic lipoproteins processed by cleavage of a conserved prolipoprotein sequence (11) and expressed as abundant surface proteins anchored on the single mycoplasma membrane by a lipid moiety on an N-terminal Cys residue. Molecular genetic analysis has shown that alternative Vlps share distinctive structural features despite divergence throughout their surface-exposed protein sequence. Structural details of known Vlps (VlpA, VlpB, and VlpC) have been defined at the g...

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“…Up to 60% of isolates from the NT do not react with available M-typing sera (28), while some react with more than one, giving an ambiguous M-typing result (27). This has led to the development of the vir typing system, which consists of restriction fragment length polymorphism analysis of the mga regulon (14).…”

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confidence: 99%

Plasminogen Binding by Group A Streptococcal Isolates from a Region of Hyperendemicity for Streptococcal Skin Infection and a High Incidence of Invasive Infection

et al. 2004

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Reports of resurgence in invasive group A streptococcal (GAS) infections come mainly from affluent populations with infrequent exposure to GAS. In the Northern Territory (NT) of Australia, high incidence of invasive GAS disease is secondary to endemic skin infection, serotype M1 clones are rare in invasive infection, the diversity and level of exposure to GAS strains are high, and no particular strains dominate. Expression of a plasminogen-binding GAS M-like protein (PAM) has been associated with skin infection in isolates elsewhere (D. Bessen, C. M. Sotir, T. M. Readdy, and S. K. Hollingshead, J. Infect. Dis. 173:896-900, 1996), and subversion of the host plasminogen system by GAS is thought to contribute to invasion in animal models. Here, we describe the relationship between plasminogen-binding capacity of GAS isolates, PAM genotype, and invasive capacity in 29 GAS isolates belonging to 25 distinct strains from the NT. In the presence of fibrinogen and streptokinase, invasive isolates bound more plasminogen than isolates from uncomplicated infections (P < 0.004). Only PAM-positive isolates bound substantial levels of plasminogen by a fibrinogen-streptokinaseindependent pathway (direct binding). Despite considerable amino acid sequence variation within the A1 repeat region of PAM where the plasminogen-binding domain maps, the critical lysine residue was conserved.Group A streptococci (GAS) cause a variety of superficial infections, such as impetigo, as well as invasive diseases, including bacteremia, necrotizing fasciitis, and myositis. A recent survey from the tropical "Top End" of the Northern Territory (NT) found a high incidence of invasive GAS disease, with rates of bacteremia in non-Aboriginal people (8) comparable to those that constituted the resurgence in GAS bacteremia described elsewhere in the Western world (29,39). Among Aboriginal people of the Top End, the incidence of GAS bacteremia is five times that of non-Aboriginal people living in the same region (8).In addition to the high incidence of severe GAS infection in the NT, several other epidemiological features characterize the GAS isolates from this vast geographic region. Up to 60% of isolates from the NT do not react with available M-typing sera (28), while some react with more than one, giving an ambiguous M-typing result (27). This has led to the development of the vir typing system, which consists of restriction fragment length polymorphism analysis of the mga regulon (14). vir typing of strains that cause GAS infection in Aboriginal communities has demonstrated that the diversity and turnover rate of these strains are much higher than those reported elsewhere (7). There has been no evidence of a resurgence in severe invasive infections due to particular strains or any invasive infection associated with M1 clones (8), which have been responsible for much of the recent resurgence in GAS bacteremia reported elsewhere (31). A recent NT study examining 100 GAS isolates found only two M1 isolates which were not clonally related or isolated fro...

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Antigenic diversity within a family of M proteins from group A streptococci: evidence for the role of frameshift and compensatory mutations

Cited by 29 publications

References 24 publications

Multilocus Sequence Typing ofStreptococcus pyogenesand the Relationships betweenemmType and Clone

Multilocus Sequence Typing ofStreptococcus pyogenesand the Relationships betweenemmType and Clone

Increased structural and combinatorial diversity in an extended family of genes encoding Vlp surface proteins of Mycoplasma hyorhinis

Plasminogen Binding by Group A Streptococcal Isolates from a Region of Hyperendemicity for Streptococcal Skin Infection and a High Incidence of Invasive Infection

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