05 was considered to be statistically significant. Lay abstract Inhalation of infectious aerosols containing viable Myco bacterium tuberculosis, results in symptomatic tuberculosis in about 5 10% of people, while the majority of exposed individuals develop asymptom atic, latent TB infection. These diverse clinical outcomes following Mtb infection are determined by intricate host pathogen Nutlin-3a IC50 interactions that are not fully understood. We have established a rabbit model of pul monary TB that closely mimics the pathological features of human disease and LTBI. In our model, pulmonary infection of rabbits with Mtb HN878, a hyper virulent W Beijing strain, results in progressive cavitary disease infection with CDC1551 is effectively cleared over time, establishing LTBI that can be reactivated upon immune suppression.

In the present study, we used our rabbit model to test the hypothesis Inhibitors,Modulators,Libraries that the initial host response in the lungs within hours of infection determines later outcome. At similar infection doses, we found increased accumulation of macrophages and PMN in the lungs of HN878, compared to CDC1551 infected rabbits, at 3 hours. Consistently, we observed activation of cellular networks involved in the inflammatory response, STAT1 activation, recruitment and activation of macrophages and PMN, and fMLP stimulation in the lungs of HN878 infected rabbits. Similar differential expression patterns in all the tested network genes were seen at 4 weeks, with infection and pathology reduced in CDC1551 infected animals compared to HN878 infection.

This suggested that the overall outcome Inhibitors,Modulators,Libraries following Mtb infection of rabbit lungs is significantly influenced by the differential regula Inhibitors,Modulators,Libraries tion of inflammation associated innate immune cells and associated gene expression changes observed already at 3 hours. Background In humans, inhalation of aerosol droplets containing Mtb results in a spectrum of clinical outcomes, ranging from progressive granulomatous disease, with continued bacil lary growth and exacerbated lung pathology, to contain ment of infection and establishment of asymptomatic latent infection. The deter minants of outcome following Mtb infection have been shown to be dependent Inhibitors,Modulators,Libraries on the host innate immune re sponse. Polymorphisms in genes encoding the toll like receptors, vitamin Inhibitors,Modulators,Libraries D receptors, and other innate immune recognition molecules have been associated with increased susceptibility of individuals to TB disease.

In addition, recent studies have suggested that the nature of the infecting bacilli also contributes to the outcome of infection. Epidemio logical studies have shown differential infectivity among various Mtb strains in the population. biological activity Genotypic analysis of 516 clinical isolates from patients showed that Mtb strains of the W Beijing lineage caused the highest num ber of TB cases in Taiwan. Similarly, a strong as sociation between W Beijing and HIV infection was reported among South African patients.