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Abstract: PO2276

Ribonuclease 6 Is an Intracellular Antimicrobial Peptide That Thwarts Bacterial Cystitis and Pyelonephritis

Session Information

Category: Pediatric Nephrology

  • 1700 Pediatric Nephrology

Authors

  • Cortado, Hanna H., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Li, Birong, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Jackson, Ashley R., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Gupta, Sudipti, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Ching, Christina B., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Spencer, John David, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Becknell, Brian, Nationwide Children's Hospital, Columbus, Ohio, United States

Group or Team Name

  • Nephrology and Urology Research Affinity Group
Background

Ribonuclease 6 (RNase 6) is a highly conserved cationic peptide with potent microbicidal activity toward uropathogenic Escherichia coli (UPEC) in vitro. Here, we determined the cellular sources of RNase 6 along with the consequences of its gain and loss of function during experimental urinary tract infection (UTI).

Methods

We generated female mice with a Rnase6EGFP knock-in allele, human RNASE6 transgene, or controls on a C57BL/6J genetic background. We identified cellular sources of RNase6 by flow cytometry and microscopy. We transurethrally inoculated Rnase6EGFP/EGFP, RNASE6 transgenic, and control mice with UPEC strain CFT073 and enumerated bacterial burden. The role of RNase 6 during intracellular killing of UPEC was investigated in bone marrow derived macrophages (BMDM) by gentamicin protection assay.

Results

Rnase6 is expressed by tissue resident macrophages and circulating monocytes that are recruited to the infected bladder and kidney within hours of UPEC inoculation. Rnase6 deficiency leads to increased renal UPEC burden relative to controls, whereas RNASE6 transgenic mice exhibit reduced UPEC burden. Rnase6 macrophages localize within the urothelium and its underlying stroma at baseline and during UTI. RNase 6 is not secreted by macrophages; instead, it is retained intracellularly within the endolysosomal system. RNASE6 over-expression in macrophages leads to increased killing of phagocytosed UPEC.

Conclusion

RNase6 is a monocyte/macrophage derived antimicrobial peptide that acts intracellularly to kill phagocytosed UPEC and limit bacterial UTI.

Funding

  • NIDDK Support