270 - A Non-Synonymous RNASE6 Polymorphism Impacts its Antimicrobial Activity and Host Susceptibility to Urinary Tract Infections

Poster Number: 270
Publication Number: 270.251

Juan de Dios Ruiz-Rosado, Nationwide Children's Hospital, Columbus, OH, United States; hanna Cortado, Nationwide Children's Hospital, columbus, OH, United States; Raúl Anguita, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Catalonia, Spain; Guillem Prats-Ejarque, ALBA Synchrotron, Cerdanyola del Vallès, Catalonia, Spain; Macie M. Kercsmar, Nationwide Children's Hospital, Westerville, OH, United States; Birong Li, Nationwide Children's Hospital, Columbus, OH, United States; Gregory Ballash, The Ohio State University, Columbus, OH, United States; Israel Cotzomi-Ortega, Nationwide Children's Hospital, Upper Arlington, OH, United States; Yuriko Sanchez-Zamora, Nationwide Children's Hospital, Columbus, OH, United States; Jorge J. Canas, Indiana University School of Medicine, Indianapolis, IN, United States; Ashley R. Jackson, Nationwide Children's Hospital, Columbus, OH, United States; Andrew Schwaderer, Indiana University School of Medicine, Indianapolis, IN, United States; David Hains, Indiana University School of Medicine, Indianapolis, IN, United States; John David Spencer, Nationwide Children's Hospital, Columbus, OH, United States; Ester Boix, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Catalonia, Spain; Brian Becknell, Ohio State University College of Medicine, Columbus, OH, United States

Background: Mounting evidence suggests that host genetic variation influences susceptibility to urinary tract infection (UTI).  RNASE6 encodes a monocyte/macrophage derived antimicrobial protein with potent activity toward uropathogenic bacteria, but the contributions of genetic variation to its antimicrobial function and UTI susceptibility remain unknown. 

Objective: Here we tested the association of the RNASE6 SNP rs1045922 with UTI in children, along with its impact on RNase 6’s antimicrobial activity toward uropathogenic Escherichia coli (UPEC).

Design/Methods: We investigated the frequency of RNASE6 SNP rs1045922 major and minor alleles among 148 non-Hispanic Caucasian females in the Careful Urinary Tract Infection Evaluation cohort and 200 matched controls. We evaluated antimicrobial properties of corresponding RNase6^R66 and RNase6^Q66 variants toward UPEC, and established RNASE6^R66 transgenic mice to test the functional role of the major allele and more potent variant in vivo.

Results: Females with UTI had increased frequency of the major RNASE6 rs1045922 allele compared to controls with no UTI. The corresponding RNase6^R66 protein exhibited superior bactericidal activity toward UPEC when compared to the RNase6^Q66 variant encoded by the minor RNASE6 rs1045922 allele. RNASE6^R66 transgenic macrophages were more proficient at intracellular UPEC killing than non-transgenic controls. When subjected to experimental cystitis, RNASE6^R66 transgenic mice developed reduced UPEC burden, mucosal injury, and inflammation compared to non-transgenic controls. 

Conclusion(s):

These results substantiate that genetic diversity in humans has yielded RNase 6 variants that differ in their antimicrobial activity toward UPEC, with a protective role for RNase6^R66 during experimental UTI.