RESUMEN
Pneumolysin (PLY) is a key Streptococcus pneumoniae virulence factor and potential candidate for inclusion in pneumococcal subunit vaccines. Dendritic cells (DC) play a key role in the initiation and instruction of adaptive immunity, but the effects of PLY on DC have not been widely investigated. Endotoxin-free PLY enhanced costimulatory molecule expression on DC but did not induce cytokine secretion. These effects have functional significance as adoptive transfer of DC exposed to PLY and antigen resulted in stronger antigen-specific T cell proliferation than transfer of DC exposed to antigen alone. PLY synergized with TLR agonists to enhance secretion of the proinflammatory cytokines IL-12, IL-23, IL-6, IL-1ß, IL-1α and TNF-α by DC and enhanced cytokines including IL-17A and IFN-γ by splenocytes. PLY-induced DC maturation and cytokine secretion by DC and splenocytes was TLR4-independent. Both IL-17A and IFN-γ are required for protective immunity to pneumococcal infection and intranasal infection of mice with PLY-deficient pneumococci induced significantly less IFN-γ and IL-17A in the lungs compared to infection with wild-type bacteria. IL-1ß plays a key role in promoting IL-17A and was previously shown to mediate protection against pneumococcal infection. The enhancement of IL-1ß secretion by whole live S. pneumoniae and by PLY in DC required NLRP3, identifying PLY as a novel NLRP3 inflammasome activator. Furthermore, NLRP3 was required for protective immunity against respiratory infection with S. pneumoniae. These results add significantly to our understanding of the interactions between PLY and the immune system.
Asunto(s)
Proteínas Portadoras/metabolismo , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Infecciones Neumocócicas/inmunología , Streptococcus pneumoniae/patogenicidad , Estreptolisinas/farmacología , Receptor Toll-Like 4/metabolismo , Animales , Proteínas Bacterianas/farmacología , Médula Ósea/inmunología , Médula Ósea/metabolismo , Médula Ósea/microbiología , Células Cultivadas , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/microbiología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/microbiología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/microbiología , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Infecciones Neumocócicas/metabolismo , Infecciones Neumocócicas/microbiología , Bazo/inmunología , Bazo/metabolismo , Bazo/microbiología , Streptococcus pneumoniae/inmunologíaRESUMEN
Many hospitals have initiated a strategy to reduce costs and improve quality of care by using physicians as "hospitalists." A hospitalist specializes in inpatient care. This article reports the findings of survey research examining CEO perceptions of the hospitalist model, with particular interest in diffusion of the strategy in rural and low managed care hospital markets. Findings indicate there is less diffusion of the hospitalist model to rural areas because of lack of information about the cost effectiveness of the program and medical staff resistance. Recommendations to increase adoption of the hospitalist strategy include educating about the benefits of the strategy and paying attention to areas of concern by the medical staff.
