RESUMO
Coxiella burnetii is a highly infectious bacterium that promotes its own replication in macrophages by inhibiting several host cell responses. Here, we show that C. burnetii inhibits caspase-1 activation in primary mouse macrophages. By using co-infection experiments, we determine that the infection of macrophages with C. burnetii inhibits the caspase-11-mediated non-canonical activation of the NLRP3 inflammasome induced by subsequent infection with Escherichia coli or Legionella pneumophila. Genetic screening using flagellin mutants of L. pneumophila as a surrogate host, reveals a novel C. burnetii gene (IcaA) involved in the inhibition of caspase activation. Expression of IcaA in L. pneumophila inhibited the caspase-11 activation in macrophages. Moreover, icaA(-) mutants of C. burnetii failed to suppress the caspase-11-mediated inflammasome activation induced by L. pneumophila. Our data reveal IcaA as a novel C. burnetii effector protein that is secreted by the Dot/Icm type IV secretion system and interferes with the caspase-11-induced, non-canonical activation of the inflammasome.
Assuntos
Proteínas de Bactérias/imunologia , Coxiella burnetii/imunologia , Inflamassomos/imunologia , Febre Q/imunologia , Sistemas de Secreção Tipo IV/imunologia , Animais , Proteínas de Bactérias/genética , Caspases/genética , Caspases/imunologia , Caspases Iniciadoras , Coxiella burnetii/genética , Feminino , Regulação Bacteriana da Expressão Gênica , Humanos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Febre Q/genética , Febre Q/microbiologia , Sistemas de Secreção Tipo IV/genéticaRESUMO
Coxiella burnetii is an obligate intracellular bacterium that generates large vacuoles in which this pathogen replicates and survives. We have previously demonstrated that C. burnetii interacts with the autophagic pathway as a strategy for its survival and replication. Coxiella displays an anti-apoptotic activity to maintain host cell viability, leading to a persistent infection. Our recent study reveals that Beclin 1 is recruited to the Coxiella-membrane vacuole favoring its development and bacterial replication. In contrast, the anti-apoptotic protein Bcl-2 alters the normal development of the Coxiella-replicative compartment. In addition, our results indicate that C. burnetii infection modulates autophagy and apoptotic pathways via Beclin 1-Bcl-2 interplay to establish a successful infection in the host cell. Of note, this pathogen-host cell model has allowed uncovering a novel function of Beclin 1 as a regulator of the anti-apoptotic activity of Bcl-2. We have also established that a proper interplay between Beclin 1 and Bcl-2 is required for both autophagy and apoptosis modulation.
Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Apoptose/genética , Infecções Bacterianas/patologia , Proteínas de Membrana/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Proteínas Reguladoras de Apoptose/genética , Autofagia/genética , Autofagia/fisiologia , Infecções Bacterianas/genética , Proteína Beclina-1 , Coxiella burnetii/fisiologia , Células HeLa , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Febre Q/genética , Febre Q/patologiaRESUMO
Macrophages from A/J and BALB/c mice were more susceptible to Coxiella burnetii phase II infection than were those from C57BL/6, C57BL/10, B10.A, C3H/HePas, and Swiss mice. Resistant macrophages effectively controlled the development of large replication vacuoles (LRVs), which accounted for the restriction of bacterial multiplication within the cultures. However, compared to fibroblasts, all macrophages controlled bacterial multiplication within LRVs.