Immune Cross-Opsonization within emm Clusters Following Group A Streptococcus Skin Infection

Broadening the Scope of Type-Specific Immunity

Hannah R. Frost, Delphine Laho, Martina L. Sanderson-Smith, Paul Licciardi, Susan Donath, Nigel Curtis, Joseph Kado, James Dale, Andrew C. Steer, Pierre R. Smeesters

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1523-1531
Number of pages9
JournalClinical Infectious Diseases
Volume65
Issue number9
DOIs
StatePublished - Nov 1 2017

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Streptococcus
Immunity
Skin
Infection
Serum
Antibodies
Vaccines
Impetigo
Developing Countries
Enzyme-Linked Immunosorbent Assay
Proteins
retinal S antigen peptide M

All Science Journal Classification (ASJC) codes

  • Microbiology (medical)
  • Infectious Diseases

Cite this

Frost, H. R., Laho, D., Sanderson-Smith, M. L., Licciardi, P., Donath, S., Curtis, N., ... Smeesters, P. R. (2017). Immune Cross-Opsonization within emm Clusters Following Group A Streptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity. Clinical Infectious Diseases, 65(9), 1523-1531. https://doi.org/10.1093/cid/cix599

Immune Cross-Opsonization within emm Clusters Following Group A Streptococcus Skin Infection : Broadening the Scope of Type-Specific Immunity. / Frost, Hannah R.; Laho, Delphine; Sanderson-Smith, Martina L.; Licciardi, Paul; Donath, Susan; Curtis, Nigel; Kado, Joseph; Dale, James; Steer, Andrew C.; Smeesters, Pierre R.

In: Clinical Infectious Diseases, Vol. 65, No. 9, 01.11.2017, p. 1523-1531.

Research output: Contribution to journalArticle

Frost, HR, Laho, D, Sanderson-Smith, ML, Licciardi, P, Donath, S, Curtis, N, Kado, J, Dale, J, Steer, AC & Smeesters, PR 2017, 'Immune Cross-Opsonization within emm Clusters Following Group A Streptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity', Clinical Infectious Diseases, vol. 65, no. 9, pp. 1523-1531. https://doi.org/10.1093/cid/cix599
Frost, Hannah R. ; Laho, Delphine ; Sanderson-Smith, Martina L. ; Licciardi, Paul ; Donath, Susan ; Curtis, Nigel ; Kado, Joseph ; Dale, James ; Steer, Andrew C. ; Smeesters, Pierre R. / Immune Cross-Opsonization within emm Clusters Following Group A Streptococcus Skin Infection : Broadening the Scope of Type-Specific Immunity. In: Clinical Infectious Diseases. 2017 ; Vol. 65, No. 9. pp. 1523-1531.
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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.",
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AU - Sanderson-Smith, Martina L.

AU - Licciardi, Paul

AU - Donath, Susan

AU - Curtis, Nigel

AU - Kado, Joseph

AU - Dale, James

AU - Steer, Andrew C.

AU - Smeesters, Pierre R.

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N2 - 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.

AB - 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.

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