Proteus mirabilis

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A Microbial Biorealm page on the genus Proteus mirabilis

Classification

Higher order taxa

Kingdom: Bacteria; Phylum: Proteobacteria; Class: Gamma proteobacteria; Order: Enterobacteriales; Family: Enterobacteria; Genus: Proteus; Species: Proteus mirabilis

Species

NCBI: Taxonomy

Proteus mirabilis

Description and significance

Proteus mirabilis was first discovered by a German pathologist named Gustav Hauser (Williams and Schwarzhoff, 1978). Hauser named this genus Proteus, after the character in Homer’s The Odyssey that was good at changing shape and evading being questioned (Williams and Schwarzhoff, 1978), a name that seems apt given this organism’s uncanny ability to avoid the host’s immune system. P. mirabilis is a gram-negative, rod-shaped bacterium that can be found as part of the micro flora in the human intestine. This organism is not usually a pathogen, but does become a problem when it comes into contact with urea in the urinary tract. From there, infection can spread to other parts of the body. It is one of the species within the Proteus genus responsible for causing urinary tract infections in thousands of people each year in hospitals. P. mirabilis accounts for most of the urinary tract infections that occur in hospital settings and for ninety percent of Proteus infections (Gonzalez, 2006). Its genome codes for at least 10 adhesion factors making this organism extremely sticky and motile. P. mirabilis tests indole-negative and it can be easily identifiable in a blood agar plate by the formation of concentric rings of its swarming movement (Lund et al., 1975).

Urinary tract infections (UTIs) are very painful and can become lethal if the infection spreads to other systems in the body. After pneumonia, urinary tract infections are the most common problem in long-term hospital patients. These infections are becoming more difficult to treat because forty-eight percent of P. mirabilis strains are resistant to amoxicillin, penicillin, fluoroquinolones and other broad-range activity antibiotics.

The pH of urine is usually neutral or slightly acidic, but when a patient wears a catheter for extended periods of time crystalline deposits from the urine form a crust around the catheter and obstruct urine from moving through the urethra. The encrusted crystals on the catheter give P. mirabilis the opportunity to colonize in large numbers and to hydrolyze the urea, thus increasing the environmental pH through the production or ammonia (Stickler et al., 2004).

Genome structure

The genome sequence of P. mirabilis was completed in March 28, 2008 by Melanie M. Pearson identifying more than 3,658 coding sequences with 7 rRNA loci (Pearson et al., 2008). The genome’s total length is 4.063 Mb with a 28.8% GC content. P. mirabilis also carries a single plasmid with 36, 298 nucleotides. The plasmid itself does not contain any virulence genes but it may contain a bacteriocin and its immunity system. Within the genome is a genomic island involved in pathogenicity that codes for a type III secretion system comprising 24 genes used to inject bacterial proteins into a host genome. This type III system appears to be incorporated through horizontal gene transfer and is noted for its relatively smaller G+C content compared with the rest of the genome (Pearson et al., 2008). The genome sequence encodes 17 different types of fimbriae as well as a 54 kb flagellar regulon. The flagella made by the strain all come from a single locus. This information is characterized for a specific uropathogenic strain of P. mirabilis, HI4320. It is the first completed sequence of the bacterium out of more than 75 known strains that were identified using one dimensional SDS PAGE of cellular proteins mostly from human origin (Holmes et al., 2008).

Cell structure and metabolism

P. mirabilis has a bacillus morphology and is a gram-negative bacterium. It is motile, alternating between vegetative swimmers and hyper-flagellated swarmer cells (Belas, 1996). It also makes a variety of fimbriae. The endotoxins of its LPS membrane elicit an inflammatory response from the host. (Gonzales, 2006).

P. mirabilis produces urease, an enzyme that converts urea into ammonia by the following process: (NH₂)₂CO -> 2NH₃ + CO₂. Infection by P. mirabilis can therefore be detected by an alkaline urine sample (pH 8 and up) with large amounts of ammonia.

Ecology

P. mirabilis can be found as a free-living microbe in soil and water. The organism is also normally found in the gastrointestinal tract of humans (Coker et al., 2000). Some believe that P. mirabilis has access to the bladder by infecting the periurethral area (Coker et al., 2000). P. mirabilis causes urinary tract infections primarily through indwelling catheters. Usually the urinary tract can wash out the microbe before it accumulates, but the catheter prevents this from happening. P. mirabilis can then adhere to the insides and outsides of the catheter, forming biofilm communities. Once established, these microbes pass through the urethra via swarming motility to the bladder. P. mirabilis binds to bladder epithelial cells where it eventually colonizes (Coker et al., 2000). P. mirabilis infection can also lead to the production of kidney and bladder stones. The bacteria colonize the stones as they form, making them less accessible to antibiotic attack (Pearson et al., 2008).

Pathology

Pathogenicity of P. mirabilis is accomplished in the following two steps. First the microorganism needs to colonize the urinary tract and second, the microorganism needs to successfully evade host defenses.

Colonization of the urinary tract is done by using two of the four types of fimbriae called Mannose-resistant fimbriae (MRF) and P. mirabilis fimbriae (PMF). The importance of the MRF was determined in a study done at the Mobley lab at the University of Michigan Medical School. In their study they were able to successfully produce a nasal vaccine against MRF that worked in mice (Janson, 2003).

There are four possible mechanisms by which P. mirabilis can use to evade the host defenses. The first is production of an IgA-degrading protease which functions to cleave the secretory IgA. IgA is released by the host in an initial response to infection (Janson, 2003). The second immune system evasion mechanism is through three unique flagellin genes, which have been shown to recombine and form novel flagella capable of tricking the host’s defenses (Belas et al., 2003). The third is through expression of the MR/P fimbriae (mentioned above). They go through a process called phase variation by which the expression of flagella is found in some cells but not in others of the same population (Janson, 2003). The fourth mechanism is the urease-mediated stone formation. Production of ammonia by the action of urease results in stone formation, and these stones in turn, help protect the bacteria (Janson, 2003).

Urease and hemolysin are known to cause damage to host epithelial cells. As mentioned above, urease can damage host epithelial cells through the formation of stones. Hemolysin damages cells because of its property as a potent cytotoxin (Janson, 2003).

P. mirabilis has seven virulence factors known to aid pathogenicity. They are urease, Zap-A metalloprotease, pore-forming hemolysin, capsular polysaccharide, fimbrial types, petrichous flagella, and swarming motility (Mobley).

Application to Biotechnology

The antigens found on the outer membrane of P. mirabilis can potentially serve as targets for vaccines. So far, of the 37 identified immuno-reactive antigens, 23 are surface-bound proteins. Studies have shown that 2 iron acquisition proteins (PMI0842 and PMI2596) increase the virulence of P. mirabilis in the urinary tract (Nielubowicz et al., 2008). Since both of these proteins contribute to pathogenesis, they are good candidates for vaccines. Once an effective vaccine is made for these antigens, further research will determine whether or not these vaccines may be used against other bacteria that cause complicated urinary tract infections, such as Providencia and Morganella (Nielubowicz et al. 2008).

Current Research

P. mirabilis makes several different fimbriae that promote adhesion to mucosal surfaces. One of these fimbriae, called the mannose resistant Proteus-like fimbriae, has been highly present in patients associated with urinary tract infections (Xin et al., 1999). A mannose resistant Proteus-like gene (mrpH) present in the mrp operon of mrp fimbrae has been recently shown to be essential for functional adhesion of MR/P fimbrae(Xin etc. al, 1999). By using insertional mutagenesis, researchers noted that without the functional gene mrpH, there was less MR/P fimbriation. This information led to the conclusion that further research into the capabilities of the mrpH gene could lead to the production of a vaccine to render this gene ineffective. This would ultimately halt the ability of the Proteus mirabilis bacterium from attaching to mucosal surfaces, hindering infection (Xin et al., 1999).

P. mirabilis can be commonly present in healthy individuals as part of the normal mucosa. The bacterium becomes a significant problem mostly in individuals that have vulnerable immune systems and are in danger of nosocomial transmission, such as hospital patients (Farkosh et al., 2008). Current studies show that there are a number of antibiotics that were once effective against P. mirabilis that are now useless due to extended spectrum beta lactamases (ESBLs). These are enzymes passed through plasmids and are found in most of the Enterobacteriaceae. These plasmids were found within abscesses, blood, catheter tips, lung, peritoneal fluid, sputum, and throat culture (Farkosh et al., 2008). Detected in the 1980’s in Klebsiella and E. coli, these enzymes were found to hydrolyze antibiotic cephalosporin thus making it ineffective. The ESBL’s become highly dangerous when produced in copious amounts, conveying resistance to a large number of antibiotics used universally. The spread of these plasmids is primarily prevalent in healthcare facilities where patients have extended hospital stays, are using catheters, are within the ICU, have had recent surgery or are administered consistently with antibiotics.

References

Belas, R. "Proteus mirabilis Swarmer Cell Differentiation and Urinary Tract Infection in Urinary Tract Infections: Molecular Pathogenesis and Clinical Management." J.W. Warren, Editor. 1996, ASM Press: Washington, D.C. p. 271-298.

Coker, Christopher, Carrie A. Poore, Xin Li, Harry L.T. Mobley. “Pathogenesis of Proteus mirabilis urinary tract infection.” Microbes and Infection. 2 (2000): 1497-1505.

Farkosh, S. Mary. “Extended-Spectrum beta-lactamase Producing Gram Negative Bacilli”. 2000. JHH HEIC. November 21, 2008. www.nosoweb.org/infectious_diseases/esbl.htm

Gonzales, Gus. Proteus Infections. eMedicine from WebMD. Last edited 2 March 2006. Accessed Nov. 30, 2008.<http://www.emedicine.com/med/TOPIC1929.HTM>

Holmes, B., M. Costas, and AC Wood. "Typing of Proteus mirabilis from clinical sources by computerized analysis of electrophoretic protein patterns." Pub Med. Nov. 1991. NCBI. 21 Nov. 2008 <http://www.ncbi.nlm.nih.gov/pubmed/>.

Janson, Anglea M., Victoria Lockatell, David E. Johnson, and Harry L. Mobley. "Visualization of Proteus Mirabilis Morphotypes in the Urinary Tract: the Elongated Swarmer Cell is Rarely Observed in Ascending Urinary Tract Infection." Infection and Immunity (2003): 3607-13.

Li, Xin; Johnson, E. David; and Mobley L.T Harry. “Requirement of MrpH for Mannose-Resistant Proteus-Like Fimbria-Mediated Hemagglutination by Proteus mirabilis”. American society of Microbiology. Infect Immun. 1999 June; 67(6): 2822–2833. [PubMed]

Lund, Marlys E., John M. Matsen, Donna J. Blazevic. "Rapid Identification of Swarming Proteus Using thePathoTec Ornithine Decarboxylase Test Strip." Journal of Clinical Microbiology. May 1975, P. 478-9.

Nielubowicz, Greta R., Sara N. Smith, Harry L.T. Mobley. “Outer membrane antigens of the uropathogen Proteus mirabilis recognized by the humoral response during experimental murine urinary tract infection.” Infection and Immunity. 76.9 (2008): 4222-31.

Pearson MM, Sebaihia M, Churcher C, Quail MA, Seshasayee AS, Luscombe NM, Abdellah Z, Arrosmith C, Atkin B, Chillingworth T, Hauser H, Jagels K, Moule S, Mungall K, Norbertczak H, Rabbinowitsch E, Walker D, Whithead S, Thomson NR, Rather PN, Parkhill J, Mobley HL. “Complete genome sequence of uropathogenic Proteus mirabilis, a master of both adherence and motility.” J Bacteriol. 190.11 (2008): 4027-37.

"Proteus mirabilis: Model for Pathogenesis in the Urinary Tract." Mobley Research Laboratory. University of Michigan Medical School. 29 Nov. 2008 <http://www.umich.edu/~hltmlab/research/mirabillis/model.htm>.

"Proteus mirabilis." NationMaster. 6 Dec. 2008 <http://www.nationmaster.com/encyclopedia/proteus-mirabilis>.

Stickler, D.J, et al. Observations on the adherence of Proteus mirabilis onto polymer surfaces. Journal of Applied Microbiology. Accepted 24 October 2005. pp. 1028–1033

Williams, F.D. and R.H. Schwarzhoff, Nature of the swarming phenomenon in Proteus. Annu Rev Microbiol, 1978. 32: p. 101-22.

Edited by Isioma Agboli, Michael Cao, Janice Love, and Fatima Morales, students of Dr. Maia Larios-Sanz at University of St. Thomas