Gene-dose-dependent roles of <i>DEFA1A3</i>in the neutralization of uropathogenic <i>Escherichia coli</i>

Abstract Genetic polymorphisms of the human genome provide information about disease susceptibility and autoimmunity. variations involving innate immune system have potential to improve effectiveness diagnosis treatment urinary tract infections in children adults. DNA copy number (CNVs) DEFA1A3, which encodes for antimicrobial peptides α-defensin 1–3, been associated with recurrent UTI risk vesicoureteral reflux (VUR). α-Defensins 1–3 are pleiotropic bactericidal immunomodulatory properties. Due absence a gene ortholog mice, traditional murine models study effect DEFA1A3CNVs lacking. Our objective is explore gene-dosage effects DEFA1A3locus by utilizing UTI-challenged transgenic mouse model expressing variable copies gene. To UTIs, uropathogenic E. coli(UPEC) pyelonephritis strain (CFT073) or vehicle volume was injected transurethrally into DEFA4/4, DEFA4/0, DEFA0/0mice. Urinary organs were analyzed quantifiable bacterial growth, cell frequencies, response expression array. Kidney clearance proportional gene-dosage; gradually decreasing colonization mice between DEFA4/4(71%), DEFA4/0(57%), DEFA0/0(43%) genotypes. The kidney cells displayed differential mRNA pro-inflammatory genes Il1βand Il6genes as well phagocytic Rac1and Lyz2between infected findings support protective roles DEFA1A3gene UTI-induced pyelonephritis. Supported grants from NIH (R01 DK117934 &amp; R01 DK106286 )