NOD2 is dispensable for ATG16L1 deficiency-mediated resistance to urinary tract infection

Contains fulltext : 137515.pdf (publisher's version ) (Open Access)NOD2 (nucleotide-binding oligomerization domain containing 2) functions as a pathogen sensor and is involved in development of Crohn disease, a form of inflammatory bowel disease. NOD2 functions in concert with the autophagy protein ATG16L1, which is also implicated in Crohn disease. Recently, we identified a novel protective role of ATG16L1 deficiency in uropathogenic Escherichia coli-induced urinary tract infections (UTIs), which are common infectious diseases in humans. Given the known roles of NOD2 in recruiting ATG16L1 to the bacterial entry site, autophagy induction, and Crohn disease, we hypothesized that NOD2 may also play an important role in UTI pathogenesis. Instead, we found evidence that NOD2 is dispensable in the pathogenesis of UTIs in mice and humans. First, loss of Nod2 did not affect the clearance of bacteriuria and the recruitment of innate immune cells to the bladder. Second, we showed that, although nod2(-/-) mice display increased kidney abscesses in the upper urinary tract, there were no increased bacterial loads or persistence in this niche. Third, although a previous study indicates that loss of Nod2 reverses the protection from intestinal infection afforded by loss of ATG16L1 in mice, we found NOD2 deficiency did not reverse the ATG16L1-deficiency-induced protection from UTI. Finally, a population-based study of a cohort of 1819 patients did not reveal any association of NOD2 polymorphisms with UTI incidence. Together, our data indicated that NOD2 is dispensable for UTI pathogenesis in both mice and humans and does not contribute to ATG16L1-deficiency-induced resistance to UTI in mice

Recurrent urinary tract infection and risk of bladder cancer in the Nijmegen bladder cancer study

Contains fulltext : 153829.pdf (Publisher’s version ) (Open Access)BACKGROUND: Controversy exists on whether urinary tract infection (UTI) is a risk factor for urinary bladder cancer (UBC). Here, the association is investigated using data from one of the largest bladder cancer case-control studies worldwide. METHODS: Information on (i) history and age at onset of regular cystitis ('regular low-UTI') and (ii) number and age at onset of UTI treated with antibiotics ('UTI-ab') from 1809 UBC patients and 4370 controls was analysed. Odds ratios (ORs) and 95% confidence intervals (CI) adjusted for age, education, smoking, and use of aspirin/ibuprofen were generated, for men and women separately. RESULTS: Regular low-UTI was associated with an increased UBC risk (men: OR (95% CI) 6.6 (4.2-11); women: 2.7 (2.0-3.5)), with stronger effects in muscle-invasive UBC. Statistically significant decreased risks (ORs approximately 0.65) were observed for up to five UTI-ab, specifically in those who (had) smoked and experienced UTI-ab at a younger age. In women, UTI experienced after menopause was associated with a higher UBC risk, irrespective of the number of episodes. CONCLUSIONS: Regular cystitis is positively associated with UBC risk. In contrast, a limited number of episodes of UTI treated with antibiotics is associated with decreased UBC risk, but not in never-smokers and postmenopausal women

A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection

SummaryPolymorphisms in the essential autophagy gene Atg16L1 have been linked with susceptibility to Crohn’s disease, a major type of inflammatory bowel disease (IBD). Although the inability to control intestinal bacteria is thought to underlie IBD, the role of Atg16L1 during extracellular intestinal bacterial infections has not been sufficiently examined and compared to the function of other IBD susceptibility genes, such as Nod2, which encodes a cytosolic bacterial sensor. We find that Atg16L1 mutant mice are resistant to intestinal disease induced by the model bacterial pathogen Citrobacter rodentium. An Atg16L1 deficiency alters the intestinal environment to mediate an enhanced immune response that is dependent on monocytic cells, but this hyperimmune phenotype and its protective effects are lost in Atg16L1/Nod2 double-mutant mice. These results reveal an immunosuppressive function of Atg16L1 and suggest that gene variants affecting the autophagy pathway may have been evolutionarily maintained to protect against certain life-threatening infections