Bacterial determinants of persistent throat colonization and the associated immune response in a primate model of human group A streptococcal pharyngeal infection

Ashbaugh, Cameron D.; Moser, Timothy J.; Shearer, Michael H.; White, Gary L.; Kennedy, Ronald C.; Wessels, Michael R.

doi:10.1046/j.1462-5822.2000.00050.x

Cited by 86 publications

(93 citation statements)

References 38 publications

(43 reference statements)

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“…Thus, one can envisage the paradoxical situation that the M protein of S. pyogenes suppresses the local immune response by inducing Tr1-like cells, thereby favoring bacterial persistence, but also favoring a subsequent immune response that may result in rheumatic fever. Consistent with this idea, the immune response to M protein is delayed, as compared with other (extracellular) S. pyogenes Ags (50,51), possibly reflecting the ability of this protein to suppress the local immune response. Because S. pyogenes is specific for humans, in vivo studies are limited, but Chen et al (52) reported that cell wall components of S. pyogenes induce the secretion of IL-10 and TNF-␣ by human PBMCs.…”

Section: Discussionmentioning

confidence: 69%

“…This implies that, in an in vivo setting, whole M proteinexpressing bacteria or bacterial cell wall fragments might directly contact T cells during Ag presentation in lymphoid tissues and induce a Treg phenotype locally. Persistence of S. pyogenes in the human throat favors an Ab response and is required for the development of the postinfectious syndrome of rheumatic fever (50). Thus, one can envisage the paradoxical situation that the M protein of S. pyogenes suppresses the local immune response by inducing Tr1-like cells, thereby favoring bacterial persistence, but also favoring a subsequent immune response that may result in rheumatic fever.…”

Section: Discussionmentioning

confidence: 99%

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Induction of a Regulatory Phenotype in Human CD4+ T Cells by Streptococcal M Protein

Price

Schaumburg

Sandin

et al. 2005

The Journal of Immunology

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Regulatory T cells (Tregs) participate in the control of the immune response. In the human system, an IL-10-secreting, T regulatory type 1 cell (Tr1)-like subset of Tregs can be induced by concurrent cross-linking of the TCR and CD46 on naive CD4+ T cells. Because many viral and bacterial pathogens, including the major human pathogen Streptococcus pyogenes, bind to CD46, we asked whether this bacterium can directly induce Tr1-like cells through the streptococcal ligand for CD46, the M protein. The M5 and M22 proteins were found to induce T cells to develop into the IL-10-producing Tr1-like phenotype. Moreover, whole M5-expressing bacteria, but not isogenic M-negative bacteria, led to proliferation and IL-10 secretion by T cells. The interaction between the M5 protein and T cells was dependent on CD46 and the conserved C repeat region of M5. Supernatants derived from T cells stimulated with M proteins or M protein-expressing bacteria suppressed bystander T cell proliferation through IL-10 secretion. In addition, activation of CD46 through streptococcal M protein induced the expression of granzyme B, providing a second means for these cells to regulate an immune response. These findings suggest that binding to CD46 and exploiting its signaling pathway may represent a strategy employed by a number of important human pathogens to induce directly an immunosuppressive/regulatory phenotype in T cells.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Induction of a Regulatory Phenotype in Human CD4+ T Cells by Streptococcal M Protein

Price

Schaumburg

Sandin

et al. 2005

The Journal of Immunology

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“…Several GAS surface molecules in addition to the hyaluronic acid capsule have been implicated in adherence of the organisms to epithelial cells; however, these alternative adhesins failed to mediate effective colonization when the interaction between the hyaluronic acid capsule and epithelial CD44 was perturbed by a blocking antibody, by exogenous hyaluronic acid, or by reduced epithelial expression of CD44. Strains of GAS that lack a hyaluronic acid capsule adhere to epithelial cells in vitro at least as well as encapsulated strains; however, capsule-deficient strains colonize the pharynx poorly in vivo and are avirulent in experimental infection models (16,17,29). Therefore, effective colonization of the pharynx by virulent strains of GAS appears to require the specific interaction of the GAS capsular polysaccharide with CD44.…”

Section: Discussionmentioning

confidence: 99%

CD44 as a receptor for colonization of the pharynx by group A Streptococcus

Cywes

Stamenkovic²,

Wessels³

2000

J. Clin. Invest.

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122

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“…Although important information has been obtained from these studies, the inability to directly examine expression of large numbers of GAS genes over time in the posterior pharynx means that we have only a very imprecise understanding of molecular processes contributing to PHG. Several key advances have been made in recent years (24)(25)(26), but a far more detailed genetic understanding of the natural history of GAS-host interaction is needed. Thus, we analyzed the transcriptome of GAS during 86 days of upper respiratory tract interaction in 20 cynomolgus macaques.…”

mentioning

confidence: 99%

Longitudinal analysis of the group A Streptococcus transcriptome in experimental pharyngitis in cynomolgus macaques

Virtaneva

Porcella

Graham

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

200

227

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Identification of the genetic events that contribute to host-pathogen interactions is important for understanding the natural history of infectious diseases and developing therapeutics. Transcriptome studies conducted on pathogens have been central to this goal in recent years. However, most of these investigations have focused on specific end points or disease phases, rather than analysis of the entire time course of infection. To gain a more complete understanding of how bacterial gene expression changes over time in a primate host, the transcriptome of group A Streptococcus (GAS) was analyzed during an 86-day infection protocol in 20 cynomolgus macaques with experimental pharyngitis. The study used 260 custom Affymetrix (Santa Clara, CA) chips, and data were confirmed by TaqMan analysis. Colonization, acute, and asymptomatic phases of disease were identified. Successful colonization and severe inflammation were significantly correlated with an early onset of superantigen gene expression. The differential expression of two-component regulators covR and spy0680 (M1 spy0874) was significantly associated with GAS colony-forming units, inflammation, and phases of disease. Prophage virulence gene expression and prophage induction occurred predominantly during high pathogen cell densities and acute inflammation. We discovered that temporal changes in the GAS transcriptome were integrally linked to the phase of clinical disease and host-defense response. Knowledge of the gene expression patterns characterizing each phase of pathogen-host interaction provides avenues for targeted investigation of proven and putative virulence factors and genes of unknown function and will assist vaccine research.

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Bacterial determinants of persistent throat colonization and the associated immune response in a primate model of human group A streptococcal pharyngeal infection

Cited by 86 publications

References 38 publications

Induction of a Regulatory Phenotype in Human CD4+ T Cells by Streptococcal M Protein

Induction of a Regulatory Phenotype in Human CD4+ T Cells by Streptococcal M Protein

CD44 as a receptor for colonization of the pharynx by group A Streptococcus

Longitudinal analysis of the group A Streptococcus transcriptome in experimental pharyngitis in cynomolgus macaques

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