RESUMO
The exchange of information within and among bacterial populations using small diffusible molecules has been termed "quorum sensing" (QS). Due to the extracellular distribution of the QS autoinducer molecules and the evolutionary highly conserved nature of signaling components, microbial QS systems represent an excellent target for anti-infective immunotherapy. Recently, we have described the generation of quorum quenching monoclonal antibodies (mAbs) against acyl homoserine lactones (AHL) used by Pseudomonas aeruginosa as well as Staphylococcal autoinducing peptides (AIP). These mAbs suppressed QS signaling in bacteria and neutralized AHL-mediated cytotoxic effects in vitro, as well as protected animals in Staphylococcus aureus infection models.
Assuntos
Anticorpos Monoclonais/imunologia , Percepção de Quorum , Acil-Butirolactonas/imunologia , Animais , Proteínas de Bactérias/imunologia , Toxinas Bacterianas/biossíntese , Western Blotting , Bovinos , Linhagem Celular Tumoral , Células Clonais , Ensaio de Imunoadsorção Enzimática , Proteínas Hemolisinas/biossíntese , Hibridomas/imunologia , Imunização , Imunoconjugados/química , Imunoconjugados/imunologia , Camundongos , Peptídeos Cíclicos , Pseudomonas aeruginosa/citologia , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/metabolismo , Piocianina/biossíntese , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/citologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/metabolismoRESUMO
The ability to selectively induce a strong immune response against self-proteins, or increase the immunogenicity of specific epitopes in foreign antigens, would have a significant impact on the production of vaccines for cancer, protein-misfolding diseases, and infectious diseases. Here, we show that site-specific incorporation of an immunogenic unnatural amino acid into a protein of interest produces high-titer antibodies that cross-react with WT protein. Specifically, mutation of a single tyrosine residue (Tyr(86)) of murine tumor necrosis factor-alpha (mTNF-alpha) to p-nitrophenylalanine (pNO(2)Phe) induced a high-titer antibody response in mice, whereas no significant antibody response was observed for a Tyr(86) --> Phe mutant. The antibodies generated against the pNO(2)Phe are highly cross-reactive with native mTNF-alpha and protect mice against lipopolysaccharide (LPS)-induced death. This approach may provide a general method for inducing an antibody response to specific epitopes of self- and foreign antigens that lead to a neutralizing immune response.