PT  - JOURNAL ARTICLE
AU  - Canas, Jorge J
AU  - Arregui, Samuel W
AU  - Zhang, Shaobo
AU  - Knox, Taylor
AU  - Calvert, Christi
AU  - Saxena, Vijay
AU  - Schwaderer, Andrew L
AU  - Hains, David S
TI  - <em>DEFA1A3</em> DNA gene-dosage regulates the kidney innate immune response during upper urinary tract infection
AID  - 10.26508/lsa.202302462
DP  - 2024 Jun 01
TA  - Life Science Alliance
PG  - e202302462
VI  - 7
IP  - 6
4099  - http://www.life-science-alliance.org/content/7/6/e202302462.short
4100  - http://www.life-science-alliance.org/content/7/6/e202302462.full
SO  - Life Sci. Alliance2024 Jun 01; 7
AB  - Antimicrobial peptides (AMPs) are host defense effectors with potent neutralizing and immunomodulatory functions against invasive pathogens. The AMPs α-Defensin 1-3/DEFA1A3 participate in innate immune responses and influence patient outcomes in various diseases. DNA copy-number variations in DEFA1A3 have 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/DEFA1A3 copy-number variations lead to UTI susceptibility remains to be explored. In this study, we use a previously characterized transgenic knock-in of the human DEFA1A3 gene mouse to dissect α-Defensin 1-3 gene dose–dependent antimicrobial and immunomodulatory roles during uropathogenic Escherichia coli (UPEC) UTI. We elucidate the relationship between kidney neutrophil– and collecting duct intercalated cell–derived α-Defensin 1-3/DEFA1A3 expression 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 that DEFA1A3 directly protects against UPEC meanwhile impacting pro-inflammatory innate immune responses in a gene dosage–dependent manner.Primary research data, statistical analyses applied, and methodologies are provided in the study results, figure legends, and uploaded supplemental materials. All raw data are available to share with the scientific community upon request.