Effect of a bacterial pheromone peptide on host chemokine degradation in group A streptococcal necrotising soft-tissue infections

• Published in: The Lancet (British edition) 2004-02, Vol.363 (9410), p.696-703
• Main Authors: Hidalgo-Grass, Carlos, Dan-Goor, Mary, Maly, Alexander, Eran, Yoni, Kwinn, Laura A, Nizet, Victor, Ravins, Miriam, Jaffe, Joseph, Peyser, Amos, Moses, Allon E, Hanski, Emanuel
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Bacteria; Bacterial proteins; Biological and medical sciences; Chemokines - immunology; Chemotaxis, Leukocyte - immunology; Disease Models, Animal; Down-Regulation; Endopeptidases - genetics; Endopeptidases - immunology; Fasciitis, Necrotizing - immunology; Fasciitis, Necrotizing - metabolism; Fasciitis, Necrotizing - microbiology; Female; General aspects; Humans; Infections; Injection; Male; Medical sciences; Mice; Mice, Inbred BALB C; Microbiology; Neutrophil Infiltration - immunology; Pathogens; Pheromones - physiology; Proteinase inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Soft Tissue Infections - immunology; Soft Tissue Infections - metabolism; Soft Tissue Infections - microbiology; Streptococcal Infections - immunology; Streptococcal Infections - metabolism; Streptococcal Infections - microbiology; Streptococcus pyogenes - enzymology; Streptococcus pyogenes - immunology; Streptococcus pyogenes - isolation & purification; Tissues
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(04)15643-2

Necrotising soft-tissue infections due to group A streptococcus (GAS) are rare (about 0·2 cases per 100000 people). The disease progresses rapidly, causing severe necrosis and hydrolysis of soft tissues. Histopathological analysis of necrotic tissue debrided from two patients (one with necrotising fasciitis and one with myonecrosis) showed large quantities of bacteria but no infiltrating neutrophils. We aimed to investigate whether the poor neutrophil chemotaxis was linked with the ability of group A streptococcus (GAS) to degrade host chemokines. We did RT-PCR, ELISA, and dot-blot assays to establish whether GAS induces synthesis of interleukin 8 mRNA, but subsequently degrades the released chemokine protein. Class-specific protease inhibitors were used to characterise the protease that degraded the chemokine. We used a mouse model of human soft-tissue infections to investigate the pathogenic relevance of GAS chemokine degradation, and to test the therapeutic effect of a GAS pheromone peptide (SilCR) that downregulates activity of chemokine protease. The only isolates from the necrotic tissue were two β-haemolytic GAS strains of an M14 serotype. A trypsin-like protease released by these strains degraded human interleukin 8 and its mouse homologue MIP2. When innoculated subcutaneously in mice, these strains produced a fatal necrotic soft-tissue infection that had reduced neutrophil recruitment to the site of injection. The M14 GAS strains have a missense mutation in the start codon of silCR, which encodes a predicted 17 aminoacid pheromone peptide, SilCR. Growth of the M14 strain in the presence of SilCR abrogated chemokine proteolysis. When SilCR was injected together with the bacteria, abundant neutrophils were recruited to the site of infection, bacteria were cleared without systemic spread, and the mice survived. The therapeutic effect of SilCR was also obtained in mice challenged with M1 and M3 GAS strains, a leading cause of invasive infections. The unusual reduction in neutrophils in necrotic tissue of people with GAS soft-tissue infections is partly caused by a GAS protease that degrades interleukin 8. In mice, degradation can be controlled by administration of SilCR, which downregulates GAS chemokine protease activity. This downregulation increases neutrophil migration to the site of infection, preventing bacterial spread and development of a fulminant lethal systemic infection.