Streptococcal M Protein: A Multipotent and Powerful Inducer of Inflammation

Abstract

Severe infections with Streptococcus pyogenes, an important human pathogen, are associated with massive inflammatory reactions in the human host. Here we show that streptococcal M protein interacts with TLR2 on human peripheral blood monocytes. As a consequence, monocytes express the cytokines IL-6, IL-1beta, and TNF-alpha. This response is significantly increased in the presence of neutrophil-derived heparin-binding protein (HBP), which co-stimulates monocytes by interacting with CD11/CD18. Analysis of tissue biopsies from patients with necrotizing fasciitis revealed recruitment of neutrophils and monocytes to the infectious site, combined with the release of HBP. The results show that M protein, in synergy with HBP, evokes an inflammatory response that may contribute to the profound pathophysiological consequences seen in severe streptococcal infections.

Neutrophil-Derived Hyperresistinemia in Severe Acute Streptococcal Infections

“…Thus, bacterial triggers other than the classical sepsis-associated bacterial factors LPS and superantigen must be involved. One likely candidate was the streptococcal M1 protein that has recently received a lot of attention due to its immunostimulatory activity (18,26,27). Most pertinent to this study is its role as a mediator of potent activation and degranulation of neutrophils that result in vascular leakage and septic shock as well as acute lung injury (21,26).…”

Neutrophil-derived azurocidin alarms the immune system

“…Early findings by Cai and Wright [28] pointed at a possible interaction between azurocidin and ␤ 2 -integrins (CD11/CD18). In accordance, the use of a blocking antibody to CD18 abolished the azurocidin-mediated Ca 2ϩ increase completely [26], and, e.g., antibodies to Lselectin were without effect (unpublished data). As discussed earlier, immobilized azurocidin enhances the adhesion of monocytes to EC, a response that could be blocked as well with an antibody to CD18 (unpublished observation).…”

“…Following treatment with azurocidin, a strong and transient enhancement of intracellular Ca 2ϩ was observed shortly, indicating a receptor-signaling mechanism to be involved in this event [23,26]. Early findings by Cai and Wright [28] pointed at a possible interaction between azurocidin and ␤ 2 -integrins (CD11/CD18).…”

“…Labeling azurocidin with FITC seemed a suitable tool for investigating the interaction of azurocidin with white blood cells. Heinzelmann et al [25] and Påhlman et al [26] found that azurocidin binds predominantly to monocytes and to a minor extent to PMN. Binding to lymphocytes could not be detected.…”

“…Azurocidin immobilized on the endothelium may interact with in- flammatory cells in the bloodstream. In fact, it has been shown that azurocidin with preference binds to monocytes [25,26]. Once monocytes in flow recognize azurocidin presented on the endothelial surface, a mobilization of intracellular Ca 2ϩ is initiated, which is crucial for the azurocidin-mediated adhesion of monocytes [23].…”