Virulence factors

A number of specific proteins encoded by chromosomal genes have been implicated as virulence factors that allow P. mirabilis to colonize its host, evade host defenses, and cause damage to the host (Figure 3). The production of one of these proteins, urease, is a hallmark of Proteus infection. This enzyme, which catalyzes the hydrolysis of urea to carbon dioxide and ammonia, elevates urine pH to a level where normally soluble ions precipitate to form struvite or apatite stones. These stones, which form around the bacterium itself, can grow to a size that obstructs normal urine flow or prevents normal kidney function. The gene cluster encoding urease is comprised of eight genes, ureRDABCFFG. UreR encodes a transcriptional activator that induces transcription of urease genes in the presence of urea; ureABC encode the structural subunits of the enzyme itself; ureDEFG encode accessory proteins that are responsible for inserting nickel ions into the active site of the urease metalloenzyme. Mutations in the urease genes of P. mirabilis attenuate the organism; the ability of the urease-deficient P. mirabilis to colonize the urinary tract in an experimental mouse model of ascending UTI is much diminished. In addition to reduced histological damage, the formation of kidney and bladder stones is never observed for this mutant.

P. mirabilis also produces an Hptn hemolysin. This high molecular weight protein is secreted by the bacterium, resulting in lysis of erythrocytes or membrane damage to other cultured epithelial cells. The in vitro effect of the hemolysin secretion is quite dramatic. Cytotoxicity is observed within an hour of exposure of the cultured epithelial cells to hemolysin.

Fimbriae MR/P

Fimbriae MR/P

NH3 + CO?

Deaminase^ [Keto acid]3 Fe^

Deaminase^ [Keto acid]3 Fe^

IgA-degrading protease Hemolysin ■-

IgA-degrading protease Hemolysin ■-

Figure 3 Virulence factors of P. mirabilis. Proteins produced by this species that have either been demonstrated or proposed to contribute to virulence are depicted. Mutants in urease, flagella, hemolysin. MR/P fimbriae, and PMF fimbriae have been constructed and tested in a mouse model of UTI. Of these factors, urease, flagella, and MR/P fimbriae appear to contribute most significantly to virulence. Abbreviations: MR/P, mannose resistant/Proteus-like; PMF. Proteus mirabilis fimbriae; ATF. ambient temperature fimbriae; NAF, non-agglutinating fimbriae (also called uroepithelial cell adhesin).

The in vivo effects of hemolysin are less well understood. Mutations in the hemolysin structural gene (hpmA) do not appear to significantly attenuate the organism in the experimental mouse model of UTI. Its cytotoxic effect may be more subtle in vivo and cannot yet be defined as an important virulence determinant.

P. mirabilis also produces at least four kinds of fimbriae, proteinaceous surface appendages that may play a role in adherence. Fimbrial types thus far identified for P. mirabilis include the MR/P fimbria, P. mirabilis fimbria (PMF), ambient temperature fimbria (ATF), and uroepithelial cell adhesin (also called nonagglutinating fimbria, NAF). MR/P fimbria, which has received the most attention, causes agglutination of mammalian and avian erythrocytes. Mutation of the MR/P genes result in loss of fimbrial production and inability to agglutinate erythrocytes. In addition, there is a slight, but significant dimin-ishment of virulence of the organism. Numbers of bacteria recovered from infected mice drop about ten-fold in MR/P mutants. As a result, less histological damage is observed in the infected animals.

The organism also secretes an immunoglobulin A (IgA)-degrading protease and an amino acid deaminase which converts amino acids to keto acids. These keto acids are able to complex iron, and thus, may act as an iron-acquisition system for the bacterium. The contribution to virulence of the deaminase has not been determined due to the lethality of introducing this mutation into P. mirabilis.

Finally, P. mirabilis produces flagella for motility. In broth cultures, the organism produces polar flagella; on solid agar cultures, the organism converts into an elongated 'swarming cell' which produces thousands of flagella (Figure 1). Mutation of flagella genes that inactivate flagella synthesis significantly diminishes the virulence of the organism in a fashion similar to the mutation in urease. Thus, flagellum-mediated motility appears to be a critical virulence determinant for this organism.

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