Mycobacterium tuberculosis canonical virulence factors interfere with a late component of the TLR2 response.

For many intracellular pathogens, the phagosome is the site of events and interactions that shape infection outcome. Phagosomal membrane damage, in particular, is proposed to benefit invading pathogens. To define the innate immune consequences of this damage, we profiled macrophage transcriptional responses to wild-type Mycobacterium tuberculosis (Mtb) and mutants that fail to damage the phagosomal membrane. We identified a set of genes with enhanced expression in response to the mutants. These genes represented a late component of the TLR2-dependent transcriptional response to Mtb, distinct from an earlier component that included Tnf. Expression of the later component was inherent to TLR2 activation, dependent upon endosomal uptake, and enhanced by phagosome acidification. Canonical Mtb virulence factors that contribute to phagosomal membrane damage blunted phagosome acidification and undermined the endosome-specific response. Profiling cell survival and bacterial growth in macrophages demonstrated that the attenuation of these mutants is partially dependent upon TLR2. Further, TLR2 contributed to the attenuated phenotype of one of these mutants in a murine model of infection. These results demonstrate two distinct components of the TLR2 response and identify a component dependent upon endosomal uptake as a point where pathogenic bacteria interfere with the generation of effective inflammation. This interference promotes tuberculosis (TB) pathogenesis in both macrophage and murine infection models.

Coronary stenting does not improve the long-term cardiovascular outcome of patients with mild to moderate renal insufficiency.

BACKGROUND: Several studies have shown that coronary stenting reduces the frequency of clinical and angiographic restenosis in patients with mild to moderate renal insufficiency. However, less is known about the long-term benefits of stent use in this population. This study was aimed to determine the impact of coronary stenting on extended (5 years) long-term outcomes of patients with chronic renal insufficiency. METHODS: The study included 602 consecutive patients who underwent successful percutaneous coronary intervention with stenting. Renal insufficiency was defined as an estimated glomerular filtration rate < 60 ml x min(-1) x 1.73 m(-2). The major adverse cardiac events were compared for patients with (n = 160) and without (n = 442) renal insufficiency. RESULTS: After the third year of follow-up, nonfatal myocardial infarction and revascularization rates were significantly increased in patients with renal insufficiency compared with those without renal dysfunction (16.9% vs 7.7%, P = 0.001; 29.4% vs 15.8%, P < 0.001). In patients who had recurrent cardiovascular events, a significantly higher rate of de novo stenosis revascularization was found in patients with renal insufficiency than without renal insufficiency (57.7% vs 22.7%, P < 0.001), while there was no significant difference in target lesion revascularization between the groups (51.9% vs 43.6%, P = 0.323). Multivariate analysis demonstrated an independent impact of the presence of renal insufficiency on the major adverse cardiac events (hazard ratio: 1.488, 95% confidence interval: 1.051 - 2.106, P = 0.025) and de novo stenosis (hazard ratio: 5.505, 95% confidence interval: 2.151 - 14.090, P < 0.001). CONCLUSIONS: The late major adverse cardiac events, after successful coronary stenting, is increased in patients with an estimated glomerular filtration rate < 60 ml x min(-1) x 1.73 m(-2). This might be associated with increased risk of de novo stenosis in this population.