Abstract
Proteus mirabilis (PM) is a Gram-negative rod-shaped bacterium and widely exists in the natural environment, and it is most noted for its swarming motility and urease activity. PM is the main pathogen causing complicated urinary tract infections (UTIs), especially catheter-associated urinary tract infections. Clinically, PM can form a crystalline biofilm on the outer surface and inner cavity of the urethral indwelling catheter owing to its ureolytic biomineralization. This leads to catheter encrustation and blockage and, in most cases, is accompanied by urine retention and ascending UTI, causing cystitis, pyelonephritis, and the development of bladder or kidney stones, or even fatal complications such as septicemia and endotoxic shock. In this review, we discuss how PM is mediated by a catheter into the urethra, bladder, and then rose to the kidney causing UTI and the main virulence factors associated with different stages of infection, including flagella, pili or adhesins, urease, hemolysin, metal intake, and immune escape, encompassing both historical perspectives and current advances.
References
1.
Stamm
WE
, Norrby
SR
. Urinary tract infections: disease panorama and challenges
. J Infect Dis
. 2001
;183
(Suppl 1
):S1
–4
. 2.
Kranz
J
, Schmidt
S
, Lebert
C
, Schneidewind
L
, Mandraka
F
, Kunze
M
, et al. The 2017 update of the German clinical guideline on epidemiology, diagnostics, therapy, prevention, and management of uncomplicated urinary tract infections in adult patients: part 1
. Urol Int
. 2018
;100
(3
):263
–70
. .3.
Harrabi
H
. Uncomplicated urinary tract infection
. N Engl J Med
. 2012
;367
(2
):185
. author reply 85
. .4.
Nielubowicz
GR
, Mobley
HL
. Host-pathogen interactions in urinary tract infection
. Nat Rev Urol
. 2010
;7
(8
):430
–41
. .5.
Kranz
J
, Schmidt
S
, Lebert
C
, Schneidewind
L
, Mandraka
F
, Kunze
M
, et al. The 2017 update of the German clinical guideline on epidemiology, diagnostics, therapy, prevention, and management of uncomplicated urinary tract infections in adult patients. Part II: therapy and prevention
. Urol Int
. 2018
;100
(3
):271
–8
. .6.
Lichtenberger
P
, Hooton
TM
. Complicated urinary tract infections
. Curr Infect Dis Rep
. 2008
;10
(6
):499
–504
. .7.
Drzewiecka
D
. Significance and roles of Proteus spp. bacteria in natural environments
. Microb Ecol
. 2016
;72
(4
):741
–58
. .8.
Yatsunenko
T
, Rey
FE
, Manary
MJ
, Trehan
I
, Dominguez-Bello
MG
, Contreras
M
, et al. Human gut microbiome viewed across age and geography
. Nature
. 2012
;486
(7402
):222
–7
. .9.
Sabbuba
NA
, Mahenthiralingam
E
, Stickler
DJ
. Molecular epidemiology of Proteus mirabilis infections of the catheterized urinary tract
. J Clin Microbiol
. 2003
;41
(11
):4961
–5
. .10.
Jacobsen
SM
, Stickler
DJ
, Mobley
HL
, Shirtliff
ME
. Complicated catheter-associated urinary tract infections due to Escherichia coli and Proteus mirabilis
. Clin Microbiol Rev
. 2008
;21
(1
):26
–59
. .11.
Nicolle
L
. Catheter-related urinary tract infection
. Drugs Aging
. 2005
;22
(8
):627
–39
. .12.
O’Hara
C
, Brenner
F
, Miller
J
. Classification, identification, and clinical significance of Proteus, Providencia, and Morganella
. Clin Microbiol Rev
. 2000
;13
(4
):534
–46
.13.
Jones
SM
, Yerly
J
, Hu
Y
, Ceri
H
, Martinuzzi
R
. Structure of Proteus mirabilis biofilms grown in artificial urine and standard laboratory media
. FEMS Microbiol Lett
. 2007
;268
(1
):16
–21
. .14.
Chen
CY
, Chen
YH
, Lu
PL
, Lin
WR
, Chen
TC
, Lin
CY
. Proteus mirabilis urinary tract infection and bacteremia: risk factors, clinical presentation, and outcomes
. J Microbiol Immunol Infect
. 2012
;45
(3
):228
–36
. .15.
Vaidyanathan
S
, Soni
BM
, Hughes
PL
, Singh
G
, Oo
T
. Severe ventral erosion of penis caused by indwelling urethral catheter and inflation of Foley balloon in urethra-need to create list of “never events in spinal cord injury” in order to prevent these complications from happening in paraplegic and tetraplegic patients
. Adv Urol
. 2010
:461539
. .16.
Mathur
S
, Sabbuba
NA
, Suller
MT
, Stickler
DJ
, Feneley
RC
. Genotyping of urinary and fecal Proteus mirabilis isolates from individuals with long-term urinary catheters
. Eur J Clin Microbiol Infect Dis
. 2005
;24
(9
):643
–4
. .17.
Garcia
MM
, Gulati
S
, Liepmann
D
, Stackhouse
GB
, Greene
K
, Stoller
ML
. Traditional Foley drainage systems: Do they drain the bladder?
J Urol
. 2007
;177
(1
):203
–7
; discussion 07
. .18.
Roberts
JA
, Fussell
EN
, Kaack
MB
. Bacterial adherence to urethral catheters
. J Urol
. 1990
;144
(2 Pt 1
):264
–9
. .19.
Donlan
R
. Biofilms: microbial life on surfaces
. Emerging Infect Dis
. 2002
;8
(9
):881
–90
. .20.
Downer
A
, Morris
N
, Feast
WJ
, Stickler
D
. Polymer surface properties and their effect on the adhesion of Proteus mirabilis
. Proc Inst Mech Eng H
. 2003
;217
(4
):279
–89
. .21.
Pearson
MM
, Sebaihia
M
, Churcher
C
, Quail
MA
, Seshasayee
AS
, Luscombe
NM
, et al. Complete genome sequence of uropathogenic Proteus mirabilis, a master of both adherence and motility
. J Bacteriol
. 2008
;190
(11
):4027
–37
. .22.
Scavone
P
, Iribarnegaray
V
, Caetano
AL
, Schlapp
G
, Härtel
S
, Zunino
P
. Fimbriae have distinguishable roles in Proteus mirabilis biofilm formation
. Pathog Dis
. 2016
;74
(5
):ftw033
. .23.
Mobley
HL
, Chippendale
GR
, Tenney
JH
, Mayrer
AR
, Crisp
LJ
, Penner
JL
, et al. MR/K hemagglutination of Providencia stuartii correlates with adherence to catheters and with persistence in catheter-associated bacteriuria
. J Infect Dis
. 1988
;157
(2
):264
–71
. .24.
Yakubu
DE
, Old
DC
, Senior
BW
. The haemagglutinins and fimbriae of Proteus penneri
. J Med Microbiol
. 1989
;30
(4
):279
–84
. .25.
Massad
G
, Bahrani
FK
, Mobley
HL
. Proteus mirabilis fimbriae: identification, isolation, and characterization of a new ambient-temperature fimbria
. Infect Immun
. 1994
;62
(5
):1989
–94
. .26.
Zunino
P
, Geymonat
L
, Allen
AG
, Legnani-Fajardo
C
, Maskell
DJ
. Virulence of a Proteus mirabilis ATF isogenic mutant is not impaired in a mouse model of ascending urinary tract infection
. FEMS Immunol Med Microbiol
. 2000
;29
(2
):137
–43
. .27.
Harshey
R
. Bacterial motility on a surface: many ways to a common goal
. Annu Rev Microbiol
. 2003
;57
:249
–73
. .28.
Stickler
D
, Hughes
G
. Ability of Proteus mirabilis to swarm over urethral catheters
. Eur J Clin Microbiol Infect Dis
. 1999
;18
(3
):206
–8
. .29.
Jones
GL
, Russell
AD
, Caliskan
Z
, Stickler
DJ
. A strategy for the control of catheter blockage by crystalline Proteus mirabilis biofilm using the antibacterial agent triclosan
. Eur Urol
. 2005
;48
(5
):838
–45
. .30.
Allison
C
, Lai
HC
, Hughes
C
. Co-ordinate expression of virulence genes during swarm-cell differentiation and population migration of Proteus mirabilis
. Mol Microbiol
. 1992
;6
(12
):1583
–91
. .31.
Fraser
GM
, Claret
L
, Furness
R
, Gupta
S
, Hughes
C
. Swarming-coupled expression of the Proteus mirabilis hpmBA haemolysin operon
. Microbiology
. 2002
;148
(Pt 7
):2191
–201
. .32.
Subashchandrabose
S
, Mobley
HL
. Back to the metal age: battle for metals at the host-pathogen interface during urinary tract infection
. Metallomics
. 2015
;7
(6
):935
–42
. .33.
Allison
C
, Coleman
N
, Jones
PL
, Hughes
C
. Ability of Proteus mirabilis to invade human urothelial cells is coupled to motility and swarming differentiation
. Infect Immun
. 1992
;60
(11
):4740
–6
. .34.
Allison
C
, Emödy
L
, Coleman
N
, Hughes
C
. The role of swarm cell differentiation and multicellular migration in the uropathogenicity of Proteus mirabilis
. J Infect Dis
. 1994
;169
(5
):1155
–8
. .35.
Jansen
AM
, Lockatell
CV
, Johnson
DE
, Mobley
HL
. Visualization of Proteus mirabilis morphotypes in the urinary tract: the elongated swarmer cell is rarely observed in ascending urinary tract infection
. Infect Immun
. 2003
;71
(6
):3607
–13
. .36.
Belas
R
, Flaherty
D
. Sequence and genetic analysis of multiple flagellin-encoding genes from Proteus mirabilis
. Gene
. 1994
;148
(1
):33
–41
. .37.
Belas
R
. Expression of multiple flagellin-encoding genes of Proteus mirabilis
. J Bacteriol
. 1994
;176
(23
):7169
–81
. .38.
Manos
J
, Belas
R
. Transcription of Proteus mirabilis flaAB
. Microbiology
. 2004
;150
(Pt 9
):2857
–63
. .39.
Nielubowicz
GR
, Smith
SN
, Mobley
HL
. Outer membrane antigens of the uropathogen Proteus mirabilis recognized by the humoral response during experimental murine urinary tract infection
. Infect Immun
. 2008
;76
(9
):4222
–31
. .40.
Umpiérrez
A
, Scavone
P
, Romanin
D
, Marqués
JM
, Chabalgoity
JA
, Rumbo
M
, et al. Innate immune responses to Proteus mirabilis flagellin in the urinary tract
. Microbes Infect
. 2013
;15
(10–11
):688
–96
. .41.
Legnani-Fajardo
C
, Zunino
P
, Piccini
C
, Allen
A
, Maskell
D
. Defined mutants of Proteus mirabilis lacking flagella cause ascending urinary tract infection in mice
. Microb Pathog
. 1996
;21
(5
):395
–405
. .42.
Zunino
P
, Piccini
C
, Legnani-Fajardo
C
. Flagellate and non-flagellate Proteus mirabilis in the development of experimental urinary tract infection
. Microb Pathog
. 1994
;16
(5
):379
–85
. .43.
Mobley
HL
, Belas
R
, Lockatell
V
, Chippendale
G
, Trifillis
AL
, Johnson
DE
, et al. Construction of a flagellum-negative mutant of Proteus mirabilis: effect on internalization by human renal epithelial cells and virulence in a mouse model of ascending urinary tract infection
. Infect Immun
. 1996
;64
(12
):5332
–40
. .44.
Dattelbaum
JD
, Lockatell
CV
, Johnson
DE
, Mobley
HL
. UreR, the transcriptional activator of the Proteus mirabilis urease gene cluster, is required for urease activity and virulence in experimental urinary tract infections
. Infect Immun
. 2003
;71
(2
):1026
–30
. .45.
Old
DC
, Adegbola
RA
. Haemagglutinins and fimbriae of Morganella, Proteus and Providencia
. J Med Microbiol
. 1982
;15
(4
):551
–64
. .46.
Bahrani
FK
, Cook
S
, Hull
RA
, Massad
G
, Mobley
HL
. Proteus mirabilis fimbriae: N-terminal amino acid sequence of a major fimbrial subunit and nucleotide sequences of the genes from two strains
. Infect Immun
. 1993
;61
(3
):884
–91
. .47.
Wray
SK
, Hull
SI
, Cook
RG
, Barrish
J
, Hull
RA
. Identification and characterization of a uroepithelial cell adhesin from a uropathogenic isolate of Proteus mirabilis
. Infect Immun
. 1986
;54
(1
):43
–9
. .48.
Massad
G
, Fulkerson
JF
, Watson
DC
, Mobley
HL
. Proteus mirabilis ambient-temperature fimbriae: cloning and nucleotide sequence of the aft gene cluster
. Infect Immun
. 1996
;64
(10
):4390
–5
. .49.
Schaffer
JN
, Pearson
MM
. Proteus mirabilis and urinary tract infections
. Microbiol Spectr
. 2015
;3
(5
):10.1128/microbiolspec.UTI-0017-2013
.50.
Rózalski
A
, Sidorczyk
Z
, Kotełko
K
. Potential virulence factors of Proteus bacilli
. Microbiol Mol Biol Rev
. 1997
;61
(1
):65
–89
. .51.
Sareneva
T
, Holthöfer
H
, Korhonen
TK
. Tissue-binding affinity of Proteus mirabilis fimbriae in the human urinary tract
. Infect Immun
. 1990
;58
(10
):3330
–6
. .52.
Jones
BV
, Young
R
, Mahenthiralingam
E
, Stickler
DJ
. Ultrastructure of Proteus mirabilis swarmer cell rafts and role of swarming in catheter-associated urinary tract infection
. Infect Immun
. 2004
;72
(7
):3941
–50
. .53.
Armbruster
CE
, Forsyth-DeOrnellas
V
, Johnson
AO
, Smith
SN
, Zhao
L
, Wu
W
, et al. Genome-wide transposon mutagenesis of Proteus mirabilis: essential genes, fitness factors for catheter-associated urinary tract infection, and the impact of polymicrobial infection on fitness requirements
. PLoS Pathog
. 2017
;13
(6
):e1006434
. .54.
Cook
SW
, Mody
N
, Valle
J
, Hull
R
. Molecular cloning of Proteus mirabilis uroepithelial cell adherence (UCA) genes
. Infect Immun
. 1995
;63
(5
):2082
–6
. .55.
Coker
C
, Poore
CA
, Li
X
, Mobley
HL
. Pathogenesis of Proteus mirabilis urinary tract infection
. Microbes Infect
. 2000
;2
(12
):1497
–505
. .56.
Wurpel
DJ
, Totsika
M
, Allsopp
LP
, Webb
RI
, Moriel
DG
, Schembri
MA
. Comparative proteomics of uropathogenic Escherichia coli during growth in human urine identify UCA-like (UCL) fimbriae as an adherence factor involved in biofilm formation and binding to uroepithelial cells
. J Proteomics
. 2016
;131
:177
–89
. .57.
Rocha
SP
, Pelayo
JS
, Elias
WP
. Fimbriae of uropathogenic Proteus mirabilis
. FEMS Immunol Med Microbiol
. 2007
;51
(1
):1
–7
. .58.
Mobley
HL
, Hausinger
RP
. Microbial ureases: significance, regulation, and molecular characterization
. Microbiol Rev
. 1989
;53
(1
):85
–108
. .59.
Mobley
HL
, Island
MD
, Hausinger
RP
. Molecular biology of microbial ureases
. Microbiol Rev
. 1995
;59
(3
):451
–80
. .60.
Armbruster
CE
, Smith
SN
, Yep
A
, Mobley
HL
. Increased incidence of urolithiasis and bacteremia during Proteus mirabilis and Providencia stuartii coinfection due to synergistic induction of urease activity
. J Infect Dis
. 2014
;209
(10
):1524
–32
. .61.
Armbruster
CE
, Smith
SN
, Johnson
AO
, DeOrnellas
V
, Eaton
KA
, Yep
A
, et al. The pathogenic potential of Proteus mirabilis is enhanced by other uropathogens during polymicrobial urinary tract infection
. Infect Immun
. 2017
;85
(2
):e00808
–16
. .62.
Lerner
SP
, Gleeson
MJ
, Griffith
DP
. Infection stones
. J Urol
. 1989
;141
(3 Pt 2
):753
–8
. .63.
Torzewska
A
, Różalski
A
. Various intensity of Proteus mirabilis-induced crystallization resulting from the changes in the mineral composition of urine
. Acta Biochim Pol
. 2015
;62
(1
):127
–32
. .64.
Jacobsen
SM
, Shirtliff
ME
. Proteus mirabilis biofilms and catheter-associated urinary tract infections
. Virulence
. 2011
;2
(5
):460
–5
. .65.
Morris
NS
, Stickler
DJ
, McLean
RJ
. The development of bacterial biofilms on indwelling urethral catheters
. World J Urol
. 1999
;17
(6
):345
–50
. .66.
Stickler
D
. Clinical complications of urinary catheters caused by crystalline biofilms: something needs to be done
. J Intern Med
. 2014
;276
(2
):120
–9
. .67.
Kunin
C
. Blockage of urinary catheters: role of microorganisms and constituents of the urine on formation of encrustations
. J Clin Epidemiol
. 1989
;42
(9
):835
–42
. .68.
Sabbuba
NA
, Stickler
DJ
, Mahenthiralingam
E
, Painter
DJ
, Parkin
J
, Feneley
RC
. Genotyping demonstrates that the strains of Proteus mirabilis from bladder stones and catheter encrustations of patients undergoing long-term bladder catheterization are identical
. J Urol
. 2004
;171
(5
):1925
–8
. .69.
Jansen
AM
, Lockatell
V
, Johnson
DE
, Mobley
HL
. Mannose-resistant Proteus-like fimbriae are produced by most Proteus mirabilis strains infecting the urinary tract, dictate the in vivo localization of bacteria, and contribute to biofilm formation
. Infect Immun
. 2004
;72
(12
):7294
–305
. .70.
Latta
RK
, Grondin
A
, Jarrell
HC
, Nicholls
GR
, Bérubé
LR
. Differential expression of nonagglutinating fimbriae and MR/P pili in swarming colonies of Proteus mirabilis
. J Bacteriol
. 1999
;181
(10
):3220
–5
. .71.
Alamuri
P
, Mobley
HL
. A novel autotransporter of uropathogenic Proteus mirabilis is both a cytotoxin and an agglutinin
. Mol Microbiol
. 2008
;68
(4
):997
–1017
. .72.
Alamuri
P
, Eaton
KA
, Himpsl
SD
, Smith
SN
, Mobley
HL
. Vaccination with proteus toxic agglutinin, a hemolysin-independent cytotoxin in vivo, protects against Proteus mirabilis urinary tract infection
. Infect Immun
. 2009
;77
(2
):632
–41
. .73.
Belas
R
, Manos
J
, Suvanasuthi
R
. Proteus mirabilis ZapA metalloprotease degrades a broad spectrum of substrates, including antimicrobial peptides
. Infect Immun
. 2004
;72
(9
):5159
–67
. .74.
Cassat
JE
, Skaar
EP
. Iron in infection and immunity
. Cell Host Microbe
. 2013
;13
(5
):509
–19
. .75.
Pazin
GJ
, Braude
AI
. Immobilizing antibodies in urine. II. Prevention of ascending spread of Proteus mirabilis
. Invest Urol
. 1974
;12
(2
):129
–33
.76.
Evanylo
LP
, Kadis
S
, Maudsley
JR
. Siderophore production by Proteus mirabilis
. Can J Microbiol
. 1984
;30
(8
):1046
–51
. .77.
Miles
AA
, Khimji
PL
. Enterobacterial chelators of iron: their occurrence, detection, and relation to pathogenicity
. J Med Microbiol
. 1975
;8
(4
):477
–90
. .78.
Hart
RC
, Kadis
S
, Chapman
WL
. Nutritional iron status and susceptibility to Proteus mirabilis pyelonephritis in the rat
. Can J Microbiol
. 1982
;28
(6
):713
–7
. .79.
Drechsel
H
, Thieken
A
, Reissbrodt
R
, Jung
G
, Winkelmann
G
. Alpha-keto acids are novel siderophores in the genera Proteus, Providencia, and Morganella and are produced by amino acid deaminases
. J Bacteriol
. 1993
;175
(9
):2727
–33
. .80.
Himpsl
SD
, Pearson
MM
, Arewång
CJ
, Nusca
TD
, Sherman
DH
, Mobley
HL
. Proteobactin and a yersiniabactin-related siderophore mediate iron acquisition in Proteus mirabilis
. Mol Microbiol
. 2010
;78
(1
):138
–57
. .81.
Pearson
MM
, Yep
A
, Smith
SN
, Mobley
HL
. Transcriptome of Proteus mirabilis in the murine urinary tract: virulence and nitrogen assimilation gene expression
. Infect Immun
. 2011
;79
(7
):2619
–31
. .82.
Nielubowicz
GR
, Smith
SN
, Mobley
HL
. Zinc uptake contributes to motility and provides a competitive advantage to Proteus mirabilis during experimental urinary tract infection
. Infect Immun
. 2010
;78
(6
):2823
–33
. .83.
Nakashige
TG
, Zygiel
EM
, Drennan
CL
, Nolan
EM
. Nickel sequestration by the host-defense protein human calprotectin
. J Am Chem Soc
. 2017
;139
(26
):8828
–36
. .84.
Olaitan
AO
, Morand
S
, Rolain
JM
. Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria
. Front Microbiol
. 2014
;5
:643
. .85.
Poore
CA
, Coker
C
, Dattelbaum
JD
, Mobley
HL
. Identification of the domains of UreR, an AraC-like transcriptional regulator of the urease gene cluster in Proteus mirabilis
. J Bacteriol
. 2001
;183
(15
):4526
–35
. .86.
Chromek
M
, Stankowska
D
, Dadfar
E
, Kaca
W
, Rabbani
H
, Brauner
A
. Interleukin-8 response in cells from the human urinary tract induced by lipopolysaccharides of Proteus mirabilis O3 and O18
. J Urol
. 2005
;173
(4
):1381
–4
. .87.
Callewaert
L
, Vanderkelen
L
, Deckers
D
, Aertsen
A
, Robben
J
, Michiels
CW
. Detection of a lysozyme inhibitor in Proteus mirabilis by a new reverse zymogram method
. Appl Environ Microbiol
. 2008
;74
(15
):4978
–81
. .88.
Bahrani
FK
, Mobley
HL
. Proteus mirabilis MR/P fimbrial operon: genetic organization, nucleotide sequence, and conditions for expression
. J Bacteriol
. 1994
;176
(11
):3412
–9
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