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Toll-like Receptor (TLR) 2 Mediates Inflammatory Responses to Oligomerized RrgA Pneumococcal Pilus Type 1 Protein

2012; Elsevier BV; Volume: 288; Issue: 4 Linguagem: Inglês

10.1074/jbc.m112.398875

1083-351X

Alan Basset, Fan Zhang, Cyril H. Benes, Sabina Sayeed, Muriel Herd, Claudette M. Thompson, Douglas T. Golenbock, Andrew Camilli, Richard Malley,

Respiratory viral infections research

The pneumococcal type 1 pilus is an inflammatory and adherence-promoting structure associated with increased virulence in mouse models. We show that RrgA, an ancillary pilus subunit devoid of a lipidation motif, particularly when presented as part of an oligomer, is a TLR2 agonist. The surface-exposed domain III, and in particular a 49-amino acid sequence (P3), of the protein is responsible for the TLR2 activity of RrgA. A pneumococcal mutant carrying RrgA with a deletion of the P3 region was significantly reduced in its ability to activate TLR2 and induce TNF-α responses after mouse intraperitoneal infection, whereas no such difference could be noted when TLR2−/− mice were challenged, further implicating this region in recognition by TLR2. Thus, we conclude that the type 1 pneumococcal pilus can activate cells via TLR2, and the ancillary pilus subunit RrgA is a key component of this activation.Background: The pneumococcal pilus is associated with increased inflammation.Results: A 49-amino acid region of the pilus protein RrgA activates TLR2 and is associated with increased inflammation and virulence.Conclusion: The pneumococcal pilus is a TLR2 agonist; RrgA is a key component.Significance: A better understanding of the pilus in bacterial pathogenesis is crucial for the development of novel strategies against this pathogen. The pneumococcal type 1 pilus is an inflammatory and adherence-promoting structure associated with increased virulence in mouse models. We show that RrgA, an ancillary pilus subunit devoid of a lipidation motif, particularly when presented as part of an oligomer, is a TLR2 agonist. The surface-exposed domain III, and in particular a 49-amino acid sequence (P3), of the protein is responsible for the TLR2 activity of RrgA. A pneumococcal mutant carrying RrgA with a deletion of the P3 region was significantly reduced in its ability to activate TLR2 and induce TNF-α responses after mouse intraperitoneal infection, whereas no such difference could be noted when TLR2−/− mice were challenged, further implicating this region in recognition by TLR2. Thus, we conclude that the type 1 pneumococcal pilus can activate cells via TLR2, and the ancillary pilus subunit RrgA is a key component of this activation. Background: The pneumococcal pilus is associated with increased inflammation. Results: A 49-amino acid region of the pilus protein RrgA activates TLR2 and is associated with increased inflammation and virulence. Conclusion: The pneumococcal pilus is a TLR2 agonist; RrgA is a key component. Significance: A better understanding of the pilus in bacterial pathogenesis is crucial for the development of novel strategies against this pathogen.