DEFA1A3DNA gene-dosage regulates the kidney innate immune response during upper urinary tract infection

Abstract

Antimicrobial peptides (AMPs) are host defense effectors with potent neutralizing and immunomodulatory functions against invasive pathogens. The AMPs α-Defensin 1-3/DEFA1A3participate in innate immune responses and influence patient outcomes in various diseases. DNA copy-number variations inDEFA1A3have been associated with severity and outcomes in infectious diseases including urinary tract infections (UTIs). Specifically, children with lower DNA copy numbers were more susceptible to UTIs. The mechanism of action by which α-Defensin 1-3/DEFA1A3copy-number variations lead to UTI susceptibility remains to be explored. In this study, we use a previously characterized transgenic knock-in of the humanDEFA1A3gene mouse to dissect α-Defensin 1-3 gene dose–dependent antimicrobial and immunomodulatory roles during uropathogenicEscherichia coli(UPEC) UTI. We elucidate the relationship between kidney neutrophil– and collecting duct intercalated cell–derived α-Defensin 1-3/DEFA1A3expression and UTI. We further describe cooperative effects between α-Defensin 1-3 and other AMPs that potentiate the neutralizing activity against UPEC. Cumulatively, we demonstrate thatDEFA1A3directly protects against UPEC meanwhile impacting pro-inflammatory innate immune responses in a gene dosage–dependent manner.