A Genetic Basis of Susceptibility to Acute Pyelonephritis

Background For unknown reasons, urinary tract infections (UTIs) are clustered in certain individuals. Here we propose a novel, genetically determined cause of susceptibility to acute pyelonephritis, which is the most severe form of UTI. The IL-8 receptor, CXCR1, was identified as a candidate gene when mIL-8Rh mutant mice developed acute pyelonephritis (APN) with severe tissue damage. Methods and Findings We have obtained CXCR1 sequences from two, highly selected APN prone patient groups, and detected three unique mutations and two known polymorphisms with a genotype frequency of 23% and 25% compared to 7% in controls (p<0.001 and p<0.0001, respectively). When reflux was excluded, 54% of the patients had CXCR1 sequence variants. The UTI prone children expressed less CXCR1 protein than the pediatric controls (p<0.0001) and two sequence variants were shown to impair transcription. Conclusions The results identify a genetic innate immune deficiency, with a strong link to APN and renal scarring.

[1]  Timothy A. Springer,et al.  Adhesion receptors of the immune system , 1990, Nature.

[2]  D. Canning.  Minimum incidence and diagnostic rate of first urinary tract infection. , 2000, The Journal of urology.

[3]  F. Pio,et al.  Neutrophils deficient in PU.1 do not terminally differentiate or become functionally competent. , 1998, Blood.

[4]  A. Lennartsson,et al.  AML-1, PU.1, and Sp3 regulate expression of human bactericidal/permeability-increasing protein. , 2003, Biochemical and biophysical research communications.

[5]  T. M. Maling,et al.  The pathogenesis of reflux nephropathy (chronic atrophic pyelonephritis). , 1975, The British journal of radiology.

[6]  C. Svanborg,et al.  Inherited susceptibility to acute pyelonephritis: a family study of urinary tract infection. , 2007, The Journal of infectious diseases.

[7]  R. Jonsson,et al.  A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans , 2002, Nature Genetics.

[8]  S. Nimer,et al.  Functional and Physical Interactions between AML1 Proteins and an ETS Protein, MEF: Implications for the Pathogenesis of t(8;21)-Positive Leukemias , 1999, Molecular and Cellular Biology.

[9]  J. Smellie.  Reflux and Renal Scarring , 1979 .

[10]  N. White,et al.  Natural history of recurrent urinary tract infections in women. , 1991, Reviews of infectious diseases.

[11]  Julie Simpson,et al.  Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria. , 2002, Blood.

[12]  J. Mcghee,et al.  Difference in susceptibility to gram-negative urinary tract infection between C3H/HeJ and C3H/HeN mice , 1984, Infection and immunity.

[13]  R. Gleckman,et al.  Urinary Tract Infections: Detection, Prevention, and Management By Calvin M. Kunin. 5th ed. Baltimore: Williams & Wilkins. 432 pp., illustrated. $49 , 1997 .

[14]  R Parker,et al.  Diversity of cytoplasmic functions for the 3' untranslated region of eukaryotic transcripts. , 1995, Current opinion in cell biology.

[15]  T. Heinemeyer,et al.  Databases on transcriptional regulation : TRANSFAC , TRRD and COMPEL , 1997 .

[16]  L. Hagberg,et al.  Genetic factors in host resistance to urinary tract infection , 1984, Infection.

[17]  P. Murphy,et al.  Cloning of complementary DNA encoding a functional human interleukin-8 receptor. , 1991, Science.

[18]  L. Hagberg,et al.  Genetic factors in host resistance to urinary tract infection , 1984, Infection.

[19]  J. Winberg,et al.  Studies of Urinary Tract Infections in Infancy and Childhood , 1963, Acta paediatrica Scandinavica.

[20]  W I Wood,et al.  Structure and functional expression of a human interleukin-8 receptor. , 1991, Science.

[21]  Á. Soriano,et al.  Expression of Interleukin-8 Receptors (CXCR1 and CXCR2) in Premenopausal Women with Recurrent Urinary Tract Infections , 2005, Clinical Diagnostic Laboratory Immunology.

[22]  J. Johnston,et al.  Genomic structure, characterization, and identification of the promoter of the human IL-8 receptor A gene. , 1994, Journal of immunology.

[23]  F. Anglani,et al.  Interleukin-8 and CXCR1 receptor functional polymorphisms and susceptibility to acute pyelonephritis. , 2007, The Journal of urology.

[24]  D. Nickerson,et al.  PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. , 1997, Nucleic acids research.

[25]  P. Green,et al.  Consed: a graphical tool for sequence finishing. , 1998, Genome research.

[26]  C. Svanborg,et al.  Escherichia coli induces transuroepithelial neutrophil migration by an intercellular adhesion molecule-1-dependent mechanism , 1995, Infection and immunity.

[27]  Simon A. Jones,et al.  Granulocyte chemotactic protein 2 acts via both IL‐ 8 receptors, CXCR1 and CXCR2 , 1998, European journal of immunology.

[28]  C. Kunin,et al.  Urinary Tract Infections: Detection, Prevention, and Management , 1997 .

[29]  L. Hang,et al.  Interleukin-8 receptor deficiency confers susceptibility to acute pyelonephritis. , 2001, The Journal of infectious diseases.

[30]  L. Hang,et al.  The ‘innate’ host response protects and damages the infected urinary tract , 2001, Annals of medicine.

[31]  N. Andrews,et al.  A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. , 1991, Nucleic acids research.

[32]  L. Hagberg,et al.  Evidence for separate genetic defects in C3H/HeJ and C3HeB/FeJ mice, that affect susceptibility to gram-negative infections. , 1985, Journal of immunology.

[33]  Matthias W. Hentze,et al.  Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia , 2001, Nature Genetics.

[34]  M. Bailey,et al.  HLA-B12 as a genetic marker for vesicoureteric reflux? , 1978, British medical journal.

[35]  L. Hang,et al.  Interleukin 8 Receptor Deficiency Confers Susceptibility to Acute Experimental Pyelonephritis and May Have a Human Counterpart , 2000, The Journal of experimental medicine.

[36]  B. Jacobsson,et al.  Correlation of P blood group, vesicoureteral reflux, and bacterial attachment in patients with recurrent pyelonephritis. , 1983, The New England journal of medicine.

[37]  J. Winberg,et al.  Studies of Urinary Tract Infections in Infancy and Childhood , 1963, Acta paediatrica Scandinavica.

[38]  Kazuhiko Yamamoto,et al.  SLC22A4 and RUNX1: identification of RA susceptible genes , 2004, Journal of Molecular Medicine.

[39]  J. Navarro,et al.  PU.1 Regulates the CXCR1 Promoter* , 1999, The Journal of Biological Chemistry.

[40]  P. Brenchley,et al.  Association between ICAM‐1 Gly‐Arg polymorphism and renal parenchymal scarring following childhood urinary tract infection , 2006, International journal of immunogenetics.

[41]  N. Lenny,et al.  The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation , 1995, Molecular and cellular biology.

[42]  P. Murphy,et al.  Comparison of the genomic organization and promoter function for human interleukin-8 receptors A and B. , 1994, The Journal of biological chemistry.

[43]  U. Francke,et al.  Molecular evolution of the human interleukin–8 receptor gene cluster , 1992, Nature genetics.

[44]  Yusuke Nakamura,et al.  An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis , 2003, Nature Genetics.

[45]  Béatrice Conne,et al.  The 3′ untranslated region of messenger RNA: A molecular ‘hotspot’ for pathology? , 2000, Nature Medicine.

[46]  A. Birch‐Andersen,et al.  Ultrastructural localization of capsules, cell wall polysaccharide, cell wall proteins, and F antigen in pneumococci , 1988, Infection and immunity.

[47]  Jurg Ott,et al.  A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis , 2003, Nature Genetics.

[48]  L. Hang,et al.  Interleukin-8 receptor knockout mice have subepithelial neutrophil entrapment and renal scarring following acute pyelonephritis. , 2000, The Journal of infectious diseases.

[49]  C. Svanborg,et al.  Natural history of renal scarring in susceptible mIL-8Rh-/- mice. , 2005, Kidney international.

[50]  Wei Sun,et al.  Expression and significance of ICAM-1 and its counter receptors LFA-1 and Mac-1 in experimental acute pancreatitis of rats. , 2006, World journal of gastroenterology.

[51]  U. Jodal,et al.  Urinary infection, reflux and renal scarring in females continuously followed for 13–38 years , 1995, Pediatric Nephrology.

[52]  S. Collins,et al.  Terminal differentiation of human promyelocytic leukemia cells induced by dimethyl sulfoxide and other polar compounds. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[53]  W. Modi,et al.  Assignment of genes for interleukin-8 receptors (IL8R) A and B to human chromosome band 2q35. , 1993, Cytogenetics and Cell Genetics.

[54]  R. Cotran,et al.  The role of endothelial cells in inflammation. , 1990, Transplantation.

[55]  K. Sirotkin,et al.  dbSNP-database for single nucleotide polymorphisms and other classes of minor genetic variation. , 1999, Genome research.