title: NOD2 is dispensable for ATG16L1 deficiency-mediated resistance to urinary tract infection.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology; Washington University School of Medicine; St Louis, MO USA.
authors.forename: Caihong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology; Washington University School of Medicine; St Louis, MO USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Obstetrics and Gynecology; Washington University School of Medicine; St Louis, MO USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Ma
authors.affiliation: Department of Obstetrics and Gynecology; Washington University School of Medicine; St Louis, MO USA.
authors.forename: Graziella R
authors.initials: GR
authors.lastname: Mendonsa
authors.affiliation: Department of Medicine; Radboud University Nijmegen Medical Centre; Nijmegen, Netherlands.
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.affiliation: Department for Health Evidence/Department of Urology; Radboud University Nijmegen Medical Centre; Nijmegen, Netherlands.
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.affiliation: Department for Health Evidence/Department of Human Genetics; Radboud University Nijmegen Medical Centre; Nijmegen, Netherlands.
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.affiliation: Department of Obstetrics and Gynecology; Washington University School of Medicine; St Louis, MO USA; Department of Pathology and Immunology; Washington University School of Medicine; St Louis, MO USA.
authors.forename: Indira U
authors.initials: IU
authors.lastname: Mysorekar
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003424:Crohn Disease / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000172:deficiency / Q000378:metabolism*; D014552:Urinary Tract Infections / Q000235:genetics / Q000378:metabolism*
chemical_list: C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D053473:Nod2 Signaling Adaptor Protein
keywords: Crohn disease; G908R; L1007finsC; NLR; R702W; bladder; kidney; pyelonephritis; uropathogenic E. coli