Kidney Week

Abstract: SA-PO431

The Ribonuclease Inhibitor Regulates the Host Immune Response to Uropathogenic Escherichia coli

Session Information

• Pediatric Nephrology - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

• 1600 Pediatric Nephrology

Authors

• Cortado, Hanna H., Nationwide Children's Hospital, Columbus, Ohio, United States

Hanna H. Cortado,

• Gupta, Sudipti, Nationwide Childrens Hospital , Columbus, Ohio, United States

Sudipti Gupta,

• Li, Birong, Nationwide Children's Hospital, Columbus, Ohio, United States

Birong Li,

• Jackson, Ashley R., Nationwide Children's Hospital, Columbus, Ohio, United States

Ashley R. Jackson,

• Ching, Christina B., Nationwide Children''s Hospital, Columbus, Ohio, United States

Christina B. Ching,

• Becknell, Brian, Nationwide Children's Hospital, Columbus, Ohio, United States

Brian Becknell,

Background

The Ribonuclease (RNase) A Superfamily encodes cationic antimicrobial peptides with bactericidal activity toward uropathogens. The endogenous RNase Inhibitor (RI) binds to RNases with femtomolar affinity and inhibits their antimicrobial activity. Here, we tested the hypothesis that RI serves a critical role in regulating the host innate immune response during experimental urinary tract infection (UTI).

Methods

We investigated RI expression in the urinary tract by immunofluorescence microscopy and evaluation of beta-galactosidase activity in RI^LacZ reporter mice. Using Cre/LoxP recombination, we deleted RI ubiquitously (RI^△UBI) or selectively in urothelial cells (RI^△URO) or leukocytes (RI^△WBC) of adult mice. We transurethrally inoculated control and RI conditional knockout mice with uropathogenic Escherichia coli (UPEC) and enumerated bacterial burden in urinary tract tissues by homogenization and serial plating.

Results

We identified RI expression by bladder umbrella cells, renal collecting ducts, and phagocytes, all distinct sources of antimicrobial RNase secretion during UTI. Ubiquitous RI deletion led to rapid onset of erosive esophagitis and gastritis, resulting in profound weight loss and failure to thrive, precluding investigation of UTI susceptibility. RI^△URO mice were healthy and deletion of RI within umbrella cells did not lead to alterations in UPEC burden during experimental UTI. In contrast, RI^△WBC animals were protected from experimental UTI, with significantly reduced bladder UPEC burden, compared to controls.

Conclusion

RI is a negative regulator of the host leukocyte response to UPEC. Interfering with RI-RNase interactions represents a novel, rational approach to augment innate immunity during UTI.

Funding

• NIDDK Support