Mobley Research Laboratory: Department of Microbiology & Immunology: University of Michigan Medical School

Proteus mirabillis

Prevention of UTI by Vaccination

To prevent the serious consequences of infection with P. mirabilis, we are proposing to develop a multivalent vaccine that would protect against infection by this species. We believe that certain criteria make the development of a vaccine both useful and feasible.

First, its usefulness might be judged by a well defined population who would benefit from immunization. We believe that possibly three categories of patients comprise this population:

i. those with known anatomically or functionally abnormal urinary tracts, including neurogenic bladders and urinary diversions;

ii. those early in the course of long-term catheterization (urethral, suprapubic, intermittent, and condom);

iii. possibly, women with apparently normal urinary tracts but who are experiencing recurrent E. coli UTIs (before they develop P. mirabilis infection).

The latter group is included because most patients with struvite stones and recurrent urinary infection are women who do not have abnormal or instrumented urinary tracts [71]. This intimates that P. mirabilis, through the process of stone formation, can convert an uncomplicated UTI into a complicated one.

Second, infections with P.mirabilis are often difficult to clear, residing within the urease-induced crystals, a persistent reservoir for recurrent infection. Third, the combination of stones and infection may result in particularly serious renal damage including acute pyelonephritis, bacteremia and chronic pyelonephritis [12, 72]. Fourth, P. mirabilis appears to have a large number of conserved surface antigens that do not differ significantly from strain to strain, regardless of whether the bacteria are from feces, urine of asymptomatic individuals or urine of patients with catheter-associated bacteriuria or acute pyelonephritis [73]. Fifth, P. mirabilis is present in the fecal flora of <5% of individuals [74].Thus, a vaccine that clears the organism from the stool would have little effect on the normal fecal flora.

Observations from our laboratory and those of other investigators suggest that P. mirabilis vaccination may confer protection against infection with heterologous strains. At least three antigen preparations have been tested. Pelligrino [75] found that parenteral immunization with purified MR/P fimbriae protects mice from transurethral challenge with homologous and heterologous strains. We noted a strong serum immunoglobulin response to MR/P fimbriae when mice were transurethrally inoculated with P. mirabilis HI4320 [30], suggesting that this antigen is expressed in vivo and is immunogenic. We have extended these studies using components of the MR/P fimbriae (see specific study below). An outer membrane protein preparation was used by O'Hanley's group [76] to protect Balb/C mice from homologous intravesicular challenge. In addition, many years ago, Braude [77] immunized rats parenterally with purified flagella. He demonstrated that antiserum immobilized bacteria by binding to flagella and prevented the organisms from spreading from one kidney to the other kidney (i.e., down one ureter, into the bladder, and back up the other ureter).

Summary of Background

UTI is the most frequently diagnosed kidney and urological disorder. Those with structural abnormalities of the urinary tract or indwelling catheter are very frequently infected with P. mirabilis and other urease-positive gram-negative bacterial species [5] . Because we are beginning to understand the molecular mechanisms by which P. mirabilis establishes infection, evades the host defense, and damages host tissue, and because we can identify a large and well defined group of patients who are affected by this species, we propose to identify surface exposed proteins that are expressed in vivo and are immunogenic (or not) and use these antigens in a multivalent vaccine to prevent urinary tract infection and urolithiasis caused by P. mirabilis and related organisms. Despite these advances, no concerted effort has been made to pursue a multivalent vaccine to protect against complicated UTI.