Tamm-horsfall protein protects against urinary tract infection by proteus mirabilis

Abstract

Purpose: Proteus mirabilis is a common cause of urinary tract infection. We determined the role of Tamm-Horsfall protein as a host defense factor against the cystitis and pyelonephritis caused by P. mirabilis.

Materials and methods: We generated Tamm-Horsfall protein gene knockout mice using homologous recombination. We introduced P. mirabilis transurethrally into the bladder of Tamm-Horsfall protein deficient (THP(-/-)) and genetically similar WT (THP(+/+)) mice. We cultured urine to quantitate the degree of bacteriuria. We examined bladders and kidneys grossly and histomorphometrically to determine the intensity of inflammation.

Results: THP(-/-) mice had more severe bacteriuria and cystitis than THP(+/+) mice. THP(-/-) mice had more pyelonephritic abscesses than THP(+/+) mice. The severity of histological pyelonephritis on semiquantitative histomorphometric analysis appeared to be greater in THP(-/-) mice. The difference between the 2 groups approached but did not attain statistical significance (p = 0.053).

Conclusion: Tamm-Horsfall protein acts as a host defense factor against P. mirabilis induced urinary tract infection.

Fig. 1

Comparison of colony forming units (CFU) per milliliter of urine on day 1, day 2 and day 6 after transurethral inoculation of P. mirabilis (expressed as the log ₁₀ CFU/ml + 1) in THP^+/+ and THP^−/− mice. THP^−/− mice have more severe bacteriuria than THP^+/+ mice. * Indicates the mean.

Fig. 2

Gross appearance of nine pairs of bladders from THP^+/+ and THP^−/− mice 8 days after transurethral inoculation of P. mirabilis.

Fig. 3

The contours of the bladders were traced on the gross photographs using Neurolucida program and the inner area measured in um².

Fig. 4

Distribution of bladder area of THP^+/+ and THP^−/− mice 8 days after transurethral inoculation of P. mirabilis. * Indicates the mean.

Fig. 5

Distribution of bladder weight of THP^+/+ and THP^−/− mice 8 days after transurethral inoculation of P. mirabilis. * Indicates the mean.

Fig. 6

Representative gross morphology of THP^+/+ and THP^−/− mice bladders and kidneys 8 days after transurethral inoculation of P. mirabilis. The bladder is enlarged in THP^−/− mice (B) in comparison with THP^+/+ mice (A). Both kidneys in the THP^−/− mice (D) are severely affected in comparison with the THP^+/+ mice (C). Scale bar indicates 1 mm.

Fig. 7

Representative histology (H&E) of THP^+/+ and THP^−/− mice bladders and kidneys 8 days after transurethral inoculation of P. mirabilis (20X). (A) The THP^+/+ bladder shows well-preserved mucosa with intact transitional epithelium. No acute or chronic inflammatory cells are seen infiltrating the surface transitional epithelium. (B) The THP^−/− bladder shows severe acute inflammation with prominent acute inflammatory cell infiltrates, partial destruction of the surface transitional epithelium and surface ulceration. (C) The THP^+/+ kidney shows well-preserved architecture with all four renal compartments (glomeruli, tubules, interstitium, vessels) being intact. (D) The THP^−/− kidney reveals severe acute tubulointerstitial nephritis with abscess formation. Polymorphonuclear leukocytes are also seen throughout the tubulointerstitium outside the abscess.

Fig. 8

Histopathological grading of severity of inflammation for (A) bladder and (B) kidney from THP^+/+ and THP^−/− mice 8 days after trans-urethral inoculation of P. mirabilis (non-parametric Mann-Whitney U test, N = 10).