RESUMEN
Salmonella spp. are gram-negative flagellated bacteria that can cause food- and waterborne gastroenteritis and typhoid fever in humans. We now report that flagellin from Salmonella spp. is recognized in mouse intestine by Toll-like receptor 11 (TLR11). Absence of TLR11 renders mice more susceptible to infection by S. Typhimurium, with increased dissemination of the bacteria and enhanced lethality. Unlike S. Typhimurium, S. Typhi, a human obligatory pathogen that causes typhoid fever, is normally unable to infect mice. TLR11 is expressed in mice, but not in humans, and remarkably, we find that tlr11(-/-) mice are efficiently infected with orally administered S. Typhi. We also find that tlr11(-/-) mice can be immunized against S. Typhi. Therefore, tlr11(-/-) mice represent a small-animal model for the study of the immune response to S. Typhi and for the development of vaccines against this important human pathogen.
Asunto(s)
Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno , Ratones , Salmonella typhi , Fiebre Tifoidea/inmunología , Fiebre Tifoidea/microbiología , Animales , Flagelina/metabolismo , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Especificidad de la Especie , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismoRESUMEN
Gram-negative bacteria belonging to the Brucella species cause chronic infections that can result in undulant fever, arthritis, and osteomyelitis in humans. Remarkably, Brucella sp. genomes encode a protein, named TcpB, that bears significant homology with mammalian Toll/IL-1 receptor domains and whose expression causes degradation of the phosphorylated, signal competent form of the adapter MyD88-adapter-like (MAL). This effect of TcpB is mediated through its box 1 region and has no effect on other TLR adapter proteins such as MyD88 or TIR-domain containing adapter protein-inducing IFNbeta. TcpB also does not affect a mutant, signal-incompetent form of MAL that cannot be phosphorylated. Interestingly, the presence of TcpB leads to enhanced polyubiquitination of MAL, which is likely responsible for its accelerated degradation. A Brucella abortus mutant lacking TcpB fails to reduce levels of MAL in infected macrophages. Therefore, TcpB represents a unique pathogen-derived molecule that suppresses host innate-immune responses by specifically targeting an individual adapter molecule in the TLR signaling pathway for degradation.