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Immune Cross-Opsonization Within emm Clusters Following Group A Streptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity.

ABSTRACT: Background:Group A Streptococcus (GAS) skin infections are particularly prevalent in developing nations. The GAS M protein, by which strains are differentiated into >220 different emm types, is immunogenic and elicits protective antibodies. A major obstacle for vaccine development has been the traditional understanding that immunity following infection is restricted to a single emm type. However, recent evidence has led to the hypothesis of immune cross-reactivity between emm types. Methods:We investigated the human serological response to GAS impetigo in Fijian schoolchildren, focusing on 3 major emm clusters (E4, E6, and D4). Pre- and postinfection sera were assayed by enzyme-linked immunosorbent assay with N-terminal M peptides and bactericidal assays using the infecting-type strain, emm cluster-related strains, and nonrelated strains. Results:Twenty of the 53 paired sera demonstrated a ?4-fold increase in antibody titer against the infecting type. When tested against all cluster-related M peptides, we found that 9 of 17 (53%) paired sera had a ?4-fold increase in antibody titer to cluster-related strains as well. When grouped by cluster, the mean change to cluster-related emm types in E4 and E6 was >4-fold (5.9-fold and 19.5-fold, respectively) but for D4 was 3.8-fold. The 17 paired sera were tested in bactericidal assays against selected cluster-related and nonrelated strains. While the responses were highly variable, numerous instances of cross-reactive killing were observed. Conclusions:These data demonstrate that M type-specific and cross-reactive immune responses occur following skin infection. The cross-reactive immune responses frequently align with emm clusters, raising new opportunities to design multivalent vaccines with broad coverage.

SUBMITTER: Frost HR

PROVIDER: S-EPMC7263703 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Immune Cross-Opsonization Within emm Clusters Following Group A Streptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity.

Frost Hannah R HR Laho Delphine D Sanderson-Smith Martina L ML Licciardi Paul P Donath Susan S Curtis Nigel N Kado Joseph J Dale James B JB Steer Andrew C AC Smeesters Pierre R PR

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20171001 9

<h4>Background</h4>Group A Streptococcus (GAS) skin infections are particularly prevalent in developing nations. The GAS M protein, by which strains are differentiated into >220 different emm types, is immunogenic and elicits protective antibodies. A major obstacle for vaccine development has been the traditional understanding that immunity following infection is restricted to a single emm type. However, recent evidence has led to the hypothesis of immune cross-reactivity between emm types.<h4>M ...[more]

PMID: 29020160

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Project description:BACKGROUND: Group A streptococcus (GAS) causes a wide variety of life threatening diseases in humans and the incidence of such infections is high in developing countries like India. Although distribution of emm types of GAS in India has been described, there is a lack of data describing either the comparative distribution of emm types in throat versus skin isolates, or the distribution of certain virulence factors amongst these isolates. Therefore in the present study we have monitored the emm type pattern of Group A streptococcus throat and skin isolates from India. Additionally, the association of these isolates with closely related sic (crs), a multifunctional compliment binding virulence factor, was also explored. RESULTS: Of the 94 (46 throat and 48 skin) isolates analyzed, 37 emm types were identified. The most frequently observed emm types were emm49 (8.5%) and emm112 (7.5%) followed by 6.5% each of emm1-2, emm75, emm77, and emm81. Out of 37 emm types, 27 have been previously reported and rest were isolated for the first time in the Indian Community. The predominant emm types of throat (emm49 and emm75) samples were different from those of skin (emm44, emm81 and emm112) samples. After screening all the 94 isolates, the crs gene was found in six emm1-2 (crs1-2) isolates, which was confirmed by DNA sequencing and expression analysis. Despite the polymorphic nature of crs, no intravariation was observed within crs1-2. However, insertions and deletions of highly variable sizes were noticed in comparison to CRS isolated from other emm types (emm1.0, emm57). CRS1-2 showed maximum homology with CRS57, but the genomic location of crs1-2 was found to be the same as that of sic1.0. Further, among crs positive isolates, speA was only present in skin samples thus suggesting possible role of speA in tissue tropism. CONCLUSION: Despite the diversity in emm type pattern of throat and skin isolates, no significant association between emm type and source of isolation was observed. The finding that the crs gene is highly conserved even in two different variants of emm1-2 GAS (speA +ve and -ve) suggests a single allele of crs may be prevalent in the highly diverse throat and skin isolates of GAS in India.

Project description:BACKGROUND:The surveillance of emm types and macrolide susceptibility of group A streptococcus (GAS) in various areas and time periods enhances the understanding of the epidemiology of GAS infections and may guide treatment strategies and the formulation of type-specific vaccines. Greece has emerged as a country with high macrolide use. However, studies suggest a gradual reduction in macrolide consumption after 2007. METHODS:During a 7-year period (2011-2017), 604 GAS isolates were recovered from consecutive children presenting with pharyngeal or nonpharyngeal infections in Central Greece; 517 viable isolates underwent molecular analysis, including emm typing. RESULTS:Isolates belonged to 20 different emm types (in decreasing order of prevalence: 1, 89, 4, 12, 28, 3, 75 and 6, accounting for 88.2% of total isolates). The emm types comprised 10 emm clusters (five most common clusters: E4, A-C3, E1, A-C4 and A-C5). The emm89 isolates were acapsular ('new clade'). Overall macrolide resistance rate was 15.4%, and cMLSB emerged as the predominant resistance phenotype (56.4%). The lowest annual resistance rates occurred in 2014 (13.1%), 2016 (5.5%) and 2017(8.0%) (P for trend = 0.002). Consumption of macrolide/lincosamide/streptogramin B declined by 22.6% during 2011-2017. Macrolide resistance and emm28 and emm77 types were associated (both P<0.001). The most frequently identified genetic lineages of macrolide-resistant GAS included emm28/ST52, emm77/ST63, emm12/ST36, emm89/ST101 and emm4/ST39. We estimated that 98.8% of the isolates belonged to emm types incorporated into a novel 30-valent M protein vaccine. CONCLUSIONS:In Central Greece during 2011-2017, the acapsular emm89 isolates comprised the second most prevalent type. Susceptibility testing and molecular analyses revealed decreasing GAS macrolide resistance rates, which may be attributed to the reduction in the consumption of macrolides and/or the reduced circulation of macrolide-resistant clones in recent years. Such data may provide valuable baseline information in targeting therapeutic intervention and the formulation of type-specific GAS vaccines.

Dataset Information

Immune Cross-Opsonization Within emm Clusters Following Group A Streptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity.

Publications

Immune Cross-Opsonization Within emm Clusters Following Group A Streptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity.

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