FimH is the type 1 fimbrial tip adhesin and invasin of Escherichia coli. Its ligands are the glycans on specific proteins enriched in membrane microdomains. FimH binding shows high-affinity recognition of paucimannosidic glycans, which are shortened high-mannose glycans such as oligomannose-3 and -5. FimH can recognize equally the (single) high-mannose glycan on uroplakin Ia, on the urinary defence protein uromodulin or Tamm–Horsfall glycoprotein and on the intestinal GP2 glycoprotein present in Peyer's patches. E. coli bacteria may attach to epithelial cells via hundreds of fimbriae in a multivalent fashion. This binding is considered to provoke conformational changes in the glycoprotein receptor that translate into signalling in the cytoplasm of the infected epithelial cell. Bladder cell invasion by the uropathogenic bacterium is the prelude to recurrent and persistent urinary tract infections in humans. Patients suffering from diabetes mellitus are more prone to contract urinary tract infections. In a study of women, despite longer treatments with a more potent antibiotic, these patients also have more often recurrences of urinary tract infections compared with women without diabetes. Type 1 fimbriae are the most important virulence factors used not only for adhesion of E. coli in the urinary tract, but also for the colonization by E. coli in patients with Crohn's disease or ulcerative colitis. It appears that the increased prevalence of urinary tract infections in diabetic women is not the result of a difference in the bacteria, but is due to changes in the uroepithelial cells leading to an increased adherence of E. coli expressing type 1 fimbriae. Hypothetically, these changes are in the glycosylation of the infected cells. The present article focuses on possible underlying mechanisms for glycosylation changes in the uroepithelial cell receptors for FimH. Like diabetes, bacterial adhesion induces apoptosis that may bring the endoplasmic reticulum membrane with immature mannosylated glycoproteins to the surface. Indicatively, clathrin-mediated vesicle trafficking of glucose transporters is disturbed in diabetics, which would interfere further with the biosynthesis and localization of complex N-linked glycans.

Introduction

The human urinary tract is normally a sterile environment. However, the urinary tract is the most prevalent focus for bacteraemia. At times, bacteria invade it from the intestinal tract and cause UTIs (urinary tract infections). Women are more prone to UTIs than men because of differences in anatomy. In more than 75% of the cases, Escherichia coli is the causative agent of infection in the bladder, also called cystitis. Other bacterial agents include Klebsiella, Proteus, Enterococcus and Pseudomonas.

Type 1 fimbriae are rod-shaped extensions on the E. coli cell envelope, made of a major pilin subunit, FimA, and followed by a short flexible tip fibrillum composed of minor pilins FimF, FimG and FimH. Most E. coli express a few hundred of these proteinaceous hair-like organelles, up to 1 μm long, on their cell surface. FimH is the type 1 fimbrial adhesin and invasin of E. coli and specifically recognizes high-mannosylated glycoprotein receptors. The FimH adhesin connects with its pilin domain to FimG and is exposed with its lectin domain at the tip of the fimbriae. Type 1 fimbriae thus allow E. coli to adhere in a multivalent fashion to the superficial bladder cell lining. The attachment of type 1 fimbriae can provoke conformational changes in the mannosylated glycoprotein receptor, which subsequently translates into signalling in the cytoplasm of the infected epithelial cell and invasion of the bacteria [1]. Invasion of UPEC (uropathogenic E. coli) paired with severe early inflammatory responses is the prelude to recurrent and persistent UTIs [2]. Upon its uptake into the epithelial cells of the bladder, E. coli reaches a transiently protective environment in the superficial bladder cell in which they can grow in dynamic intracellular bacterial communities [3] or reside quiescently in underlying epithelial cell layers [4]. Upon maturation of the intracellular bacterial communities, the bacteria efflux from the infected cells, infect neighbouring cells and can consequently persist within the urinary tract. The existence of such cellular reservoirs within the urinary tract helps to explain the recurrent nature of UTIs [3].

The type 1 fimbrial FimH adhesin displays a high affinity for α-D-mannose [5]. FimH can recognize equally the single high-mannose glycan on uroplakin Ia [6] or the urinary defence protein Tamm–Horsfall glycoprotein (uromodulin) [7] and, intriguingly enough, also on the α3β1 integrin despite its presence on basolateral rather than lumen-exposed apical membranes [8]. The luminal side of the large superficial urothelial cells is seeded with the high-mannosylated uroplakin Ia receptor. When E. coli enters the bladder, the initial encounter of the bacterium with the urothelium is made with the uroplakins [1,9,10]. Uroplakin Ia is in ring-shaped complexes with three other uroplakins on the bladder epithelium and carries a single high-mannosylated glycosylation site, shown in embryonic tissue to consist of a mixture of oligomannosides-6, -7, -8 and -9 [11]. Blocking of FimH binding using mannose-based inhibitors completely inhibits binding in vitro [5] and bacterial adhesion and invasion in vivo [12].

The same virulence factors of E. coli, type 1 fimbriae carrying the FimH adhesin, recognize glycoprotein 2 that is exposed on M cells in intestinal lymphoid structures called Peyer's patches. M cells mediate transcytosis of the bacteria across the gut epithelial barrier towards dendritic cells and lymphocytes. Glycoprotein binding by FimH and subsequent transcytosis is a prerequisite to provoke a mucosal antigen-specific immune response to the invading bacteria [13]. On the other hand, abnormal expression of glycoprotein as a receptor on enterocytes for the type 1 fimbrial adhesin FimH facilitates the onset of inflammatory bowel diseases, which develop into ulcerative colitis and Crohn's disease [14]. The colitis depends both on type 1 fimbrial expression by the adherent invasive E. coli strain LF82 and on intestinal human CEACAM6 (carcinoembryonic antigen-related cell-adhesion molecule 6) expression in transgenic mice, because infection with the FimH-negative isogenic mutant of E. coli strain LF82, or of wild-type mice infected with wild-type E. coli LF82, did not induce gut inflammation. Free mannosides derived from yeast can inhibit bacterial colonization. Crohn's disease in humans may thus largely be determined by abnormal intestinal expression of (mannosylated) CEACAM6 as receptors for FimH [2,8,1217].

The N-glycans that are preferentially recognized by the FimH adhesin are paucimannosidic. This is the case not only for clinical E. coli isolates from the urinary tract (UPEC), but also for EHEC (enterohaemorrhagic E. coli) and faecal E. coli. Purified FimH lectins all have comparable affinity profiles. Regardless of their bacterial origin being uropathogenic or intestinal E. coli strains, they all display the highest affinity towards oligomannosides-3 and -5 [15]. The recent crystal structure of FimH in complex with oligomannoside-3 disclosed the molecular basis for this observation. The moiety Manα(1,3)Manβ(1,4)GlcNAcβ(1,4)GlcNAcβ of oligomannoside-3 forms a close and extended interaction with amino acid residues that are indeed conserved among E. coli strains [12,16]. An exception is the N135K mutation found in the EHEC strain O157:H7, which is functionally silent in mannose binding [17].

Patients suffering from DM (diabetes mellitus) are more prone to contract a UTI caused by the type 1 fimbriated E. coli, and the recurrence rate of UTIs in women with DM is on average 1.4 times higher compared with women without DM, despite longer treatments with a more potent initial antibiotic such as norfloxacin [18]. It appears that the increased prevalence of UTI in diabetic women is not the result of differences in virulence factors of the infecting E. coli strains, but rather due to an increased adherence of type 1 piliated E. coli [19]. Not only is the adherence of type 1 piliated E. coli higher in diabetic than in control epithelial cells, but also it was found that there is a correlation between the degree of bacterial adherence and the levels of glycated haemoglobin in the blood of the diabetic subjects. These parallel observations prompted the authors to suggest that the receptors for FimH in diabetic uroepithelial cells have different glycosylation profiles from those of healthy controls. Owing to the fact that the physiological receptors of FimH are mannosides on membrane glycoproteins and that FimH has an unusually high affinity towards high-mannose glycans [20], the current paradigm being pursued is the possible shift in the N-glycosylation profile of specific membrane receptor proteins of FimH to more of the high-mannose type in uroepithelial cells of DM patients.

Illustrations

We were interested to have a first assessment on how varying glycosylation of mammalian cells could affect the binding of UPEC. The HEK (human embryonic kidney)-293S cell line is GlcNAcT-I (N-acetylglucosaminyltransferase I)-negative and only capable of oligomannoside-5 glycosylation [21], therefore we compared the binding of bacterial strain UTI89 to HEK-293T and HEK-293S cells. The confocal microscopy recordings show that more bacteria adhere per cell to the glycan-engineered GlcNAcT-I-negative HEK-293S cell line (see Supplementary Movies S1 and S2 at http://www.biochemsoctrans.org/bst/039/bst0390349add.htm).

We also screened the glycan specificities of the E. coli type 1 fimbrial adhesin FimH on a natural glycan microarray prepared from diverse glycoprotein fractions [22,23]. Fluorescence intensities indicate the relative binding of the FimH lectin to the glycan fractions spotted on the natural glycan microarray slide. It is observed that FimH predominantly and specifically binds to oligomannosidic N-glycans (Figure 1).

Binding of FimH to a natural glycan microarray

Figure 1
Binding of FimH to a natural glycan microarray

The glycan microarray slide was prepared as described previously [22], incubated with FimH for 1 h, and bound FimH was detected using a polyclonal rabbit anti-FimH antibody followed by Alexa Fluor® 555-labelled goat anti-rabbit Ig. Each glycan sample was present in triplicate on the array, and results are means±S.D. for three data points. Structures were assigned to the bound fractions as described previously [22]. Blue square, N-acetylglucosamine; green circle, mannose; red triangle, fucose; yellow circle, galactose, yellow square, N-acetylgalactosamine; star, xylose; AA, 2-aminobenzoic acid.

Figure 1
Binding of FimH to a natural glycan microarray

The glycan microarray slide was prepared as described previously [22], incubated with FimH for 1 h, and bound FimH was detected using a polyclonal rabbit anti-FimH antibody followed by Alexa Fluor® 555-labelled goat anti-rabbit Ig. Each glycan sample was present in triplicate on the array, and results are means±S.D. for three data points. Structures were assigned to the bound fractions as described previously [22]. Blue square, N-acetylglucosamine; green circle, mannose; red triangle, fucose; yellow circle, galactose, yellow square, N-acetylgalactosamine; star, xylose; AA, 2-aminobenzoic acid.

Hypothesis

Preliminary experiments confirm our earlier findings that FimH binds with high affinity to paucimannosidic glycans, which are shortened high-mannose glycans such as oligomannosides-3 and -5 [15]. Paucimannosylated membrane proteins may be markers of a sick cell, as they are found to be repaired at the plasma membrane by chaperones reminiscent of those found in the ER (endoplasmic reticulum). For example, the activities of integrin β1, part of the heterodimeric α3β1 integrin and a FimH receptor, as indicated by its mannosides, depend on ectocalreticulin that patrols just under the plasma membrane [24]. A higher occurrence of paucimannosidic FimH receptors on metabolically compromised bladder cells could form a basis for the increased adhesion in patients with DM.

Paucimannosylation may facilitate bacterial invasion as well. This is indicated by observations that low glycan multiplicities (an overall low number of non-reducing glycan ends) and low glycan branching of receptor membrane glycan proteins subjects them to constitutive endocytosis [25]. The lesser involvement of paucimannosidic glycans in dense networks with galectins at the mucosal cell surface leads to decreased retention of mammalian cell envelope glycoproteins [26]. The endocytosis of bound UPEC along with their low glycan glycoprotein receptors may thus increase invasion rates and the chances on recurrent UTIs [27].

Hypothetically, the physiological and differentiation status of the superficial uroepithelial cells largely determines the conditions for UPEC to successfully adhere and invade by means of the type 1-fimbrial FimH adhesin. This is made plausible in a very visual manner by the observation of early electron microscopic pictures from Dr Nathan Sharon in 1993 (Figures 1 and 2 in [28]). These pictures show that not all urothelial cells are as easily and equally colonized by opportunistic pathogens and may also explain why we do not get UTIs more often. This may go as far as to explain why it is so difficult to infect healthy laboratory mice with an opportunistic extraintestinal E. coli strain, even under conditions where type 1 fimbriae are maximally expressed (phase-locked on) on the bacterial cell envelope [16].

Discussion

The dependence of UPEC on the physiological and differentiation status of the superficial uroepithelial cells for successful bacterial pathogenesis in our hypothesis is tightly linked with glycosylation changes that occur during bladder cell turnover. The bladder cell turnover events of epithelial bladder cell renewal and apoptosis are each influenced upon binding of the FimH adhesin.

UPEC can persist almost indefinitely within the immature basal cells enclosed within lysosomal and late endosomal compartments, and it has been suggested that these can re-emerge from these quiescent reservoirs to seed recurrent UTIs upon epithelial renewal [29,30]. Adherence and invasion of UPEC by means of the FimH adhesin, and commencement of the pathogenic cascade, are needed to activate the urothelial stem cell niche by the BMP4 (bone morphogenetic protein 4) signalling pathway. Immature basal cells then precociously enter the proliferative phases associated with urothelial renewal [31]. Differences in regulation and kinetics of urothelial renewal in humans may influence the progression of the UTI, towards an acute and self-limiting as opposed to a chronic type [31,32].

Binding of the chaperone–adhesin FimC–FimH complex to uroplakin Ia induces apoptosis via the phosphorylation of a threonine residue (Thr244) on the uroplakin IIIa cytoplasmic tail by protein kinase CK2 [1]. Infected bladder cells bearing the intracellular bacterial communities indeed show membrane blebbing reminiscent of apoptosis [3]. Apoptosis brings immature glycoproteins, possibly paucimannosylated, on the plasma membrane due to vesicle traffic from the Golgi and ER [32]. α-D-Mannosidic (and β-D-galactosidic) glycoproteins are increasingly exposed on apoptotic cells [33,34] and are also cleared more rapidly by macrophages because they are being recognized as apoptotic [35].

Superficial bladder cells infected with UPEC either exfoliate or support bacterial replication before UPEC fluxes back into the lumen of the bladder [27,36]. Very recently, a general mechanism has been proposed in which upon bacterial infection apoptosis is induced; however, the final stage, necrosis, is held back by integrin signalling [37]. Integrin activation at the basal membrane of the uroepithelial cells probably arrests bladder cell exfoliation, thus transforming the bladder mucosa into a bacterial residence, depending on its own colonization to prevent it from going into necrosis. In this context, it is interesting to note that FimH binding to uroplakins at the luminal epithelial membrane induces apoptosis [1], whereas FimH also binds α3β1 integrin [8] that is typically located at the basolateral membrane facing the extracellular matrix, and that the major pilin FimA has been reported to suppress host cell apoptosis by targeting mitochondria [38].

Retention in the plasma membrane of glycoprotein membrane receptors with only few N-glycosylation sites (low multiplicity), such as TGFβ (transforming growth factor β) receptor, cytotoxic T-lymphocyte-associated antigen-4 and GLUT4 (glucose transporter 4), is regulated by their glycosylation [25]. These low-multiplicity N-glycosylated membrane proteins show rapid responses to increasing hexosamine (GlcNAc) concentration, reflecting the Golgi pathway for complex glycan formation and glycan branching [25,39]. Highly branched glycoproteins are retained more easily at the cell surface into multivalent glycan–lectin lattices [26], especially with galectin-3, a lectin that is sensitive to the branching of N-linked carbohydrates for its affinity [40].

Under a high blood glucose flux, as is the case in people with DM, complex glycan biosynthesis in the Golgi is compromised because of the prevalence of glucose over GlcNAc. Concomitantly, plasma membrane retention of low-multiplicity N-glycosylated membrane proteins is generally reduced [25]. A recent paper reports that clathrin-mediated vesicle trafficking, that relocalizes among others the glucose transporter proteins, is disturbed in DM [41]. Under normal circumstances, GLUT4 is insulin-responsive in muscle and fat cells and translocates to the plasma membrane in response to insulin signalling. This typically occurs after meals, to collect excess glucose. High blood glucose increases the presence of GLUT4 at the plasma membrane, thus increasing glycogen production and decreasing lipid metabolism [42]. When the blood glucose level is low, GLUT4 sinks back into the cytosol in specialized clathrin-coated vesicles that deliver the protein back to the membrane when the insulin signal falls. Failure to clear the high glucose concentrations enhances continuous endocytosis of GLUT4 and low surface retention in skeletal muscle, which is associated with insulin resistance in diabetics.

The TGFβ receptor is another low-N-glycosylated membrane protein receptor that experiences glycosylation-dependent surface retention. Activation of cells from a quiescent state, as happens upon the adhesion and invasion of UPEC, may promote endocytosis of low-multiplicity receptors such as the TGFβ receptor at an early stage, until lattice avidity is strengthened enough by positive feedback to the hexosamine pathway. In DM patients, a sufficient lattice avidity is, however, never reached because of the competition of high concentrations of glucose with hexosamine in complex glycan biosynthesis [26]. Consequently, the low-multiplicity glycoproteins remain under constitutive endocytosis, and the cells remain in a continuous signalling and growth status [25]. In agreement with this continuous and dysregulated cell growth, autocrine secretion of the cytokine TGFβ1 is significantly increased in glomerular mesangial cells under the high flux of D-glucose by its enzymatic conversion into D-glucosamine 6-phosphate in the hexosamine pathway [43]. Enhanced TGFβ1 secretion is responsible for the build-up of a thick extracellular matrix of heparan sulfate proteoglycan and fibronectin in the renal tubules of the kidney, in a time- and dose-dependent manner. This matrix is found laden with communities of E. coli strain UTI89 in a streptozotocin-induced diabetic mouse model of UTIs [44].

TGFβ1 is moreover activated from its latent state by a neuraminidase [45]. Interestingly, sialidases are invariably found active near the glomerular mesangial cells in diabetics [35]. Potentially, these neuraminidases help to truncate glycans to increase the exposure of α-D-mannosides and β-D-galactosides, similar to what is observed during apoptosis [34]. Glycation also plays a role in DM, but its relationship to UTIs is less well known. Standard assessment of levels of glycated haemoglobin in patients with DM measures the amount of haemoglobin to which glucose is bound in a non-enzymatic glycosylation process called glycation. Glycation is caused by the high levels of glucose in the blood and generates AGEs (advanced glycation end-products). In agreement with a host of studies documenting the involvement of AGEs in the progression and complications of diabetes, AGEs can induce apoptosis [46]. Glycosylation changes may thus form the basis of the increased adherence and invasion of urothelial cells of DM patients by type 1 fimbriated E. coli and the FimH fimbrial adhesin [19].

Conclusions

The extraction of general molecular principles governing glycan biosynthesis at cell linings and how these are affected by metabolic diseases such as DM will help to define glycomarkers as predictors of the increased occurrence and recurrence of UTIs.

Glycomarkers for Disease: An Independent Meeting held at the Conference Centre of the Polish National Academy of Sciences, Wierzba, Poland, 12–16 September 2010. Organized by Sviatlana Astrautsova (Grodno, Belarus), Cathy Merry (Manchester, U.K.), Tony Merry (Manchester, U.K.), Jean-Claude Michalski (Lille, France), Grażyna Palamarczyk (Warsaw, Poland) and Krzysztof Zwierz (Białystok, Poland). Edited by Tony Merry.

Abbreviations

     
  • AGE

    advanced glycation end-product

  •  
  • CEACAM6

    carcinoembryonic antigen-related cell-adhesion molecule 6

  •  
  • DM

    diabetes mellitus

  •  
  • EHEC

    enterohaemorrhagic Escherichia coli

  •  
  • ER

    endoplasmic reticulum

  •  
  • GlcNAcT-I

    N-acetylglucosaminyltransferase I

  •  
  • GLUT4

    glucose transporter 4

  •  
  • HEK

    human embryonic kidney

  •  
  • TGFβ

    transforming growth factor β

  •  
  • UPEC

    uropathogenic Escherichia coli

  •  
  • UTI

    urinary tract infection

Funding

A.R.d.B. was supported by the Netherlands Genomics Initiative [Horizon Breakthrough Project grant number 050-71-302]. J.B. is grateful for travel funds to the European Science Foundation workshop ‘Glycomarkers for Disease’ by the Euroglycosciences Research Forum.

References

References
1
Thumbikat
P.
Berry
R.E.
Zhou
G.
Billips
B.K.
Yaggie
R.E.
Zaichuk
T.
Sun
T.T.
Schaeffer
A.J.
Klumpp
D.J.
Bacteria-induced uroplakin signaling mediates bladder response to infection
PLoS Pathog.
2009
, vol. 
5
 pg. 
e1000415
 
2
Hannan
T.J.
Mysorekar
I.U.
Hung
C.S.
Isaacson-Schmid
M.L.
Hultgren
S.J.
Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection
PLoS Pathog.
2010
, vol. 
6
 pg. 
e1001042
 
3
Mulvey
M.A.
Schilling
J.D.
Hultgren
S.J.
Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection
Infect. Immun.
2001
, vol. 
69
 (pg. 
4572
-
4579
)
4
Mysorekar
I.U.
Mulvey
M.A.
Hultgren
S.J.
Gordon
J.I.
Molecular regulation of urothelial renewal and host defenses during infection with uropathogenic Escherichia coli
J. Biol. Chem.
2002
, vol. 
277
 (pg. 
7412
-
7419
)
5
Bouckaert
J.
Berglund
J.
Schembri
M.
De Genst
E.
Cools
L.
Wuhrer
M.
Hung
C.S.
Pinkner
J.
Slattegard
R.
Zavialov
A.
, et al. 
Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin
Mol. Microbiol.
2005
, vol. 
55
 (pg. 
441
-
455
)
6
Zhou
G.
Mo
W.J.
Sebbel
P.
Min
G.
Neubert
T.A.
Glockshuber
R.
Wu
X.R.
Sun
T.T.
Kong
X.P.
Uroplakin Ia is the urothelial receptor for uropathogenic Escherichia coli: evidence from in vitro FimH binding
J. Cell Sci.
2001
, vol. 
114
 (pg. 
4095
-
4103
)
7
Serafini-Cessi
F.
Monti
A.
Cavallone
D.
N-glycans carried by Tamm–Horsfall glycoprotein have a crucial role in the defense against urinary tract diseases
Glycoconjugate J.
2005
, vol. 
22
 (pg. 
383
-
394
)
8
Eto
D.S.
Jones
T.A.
Sundsbak
J.L.
Mulvey
M.A.
Integrin-mediated host cell invasion by type 1-piliated uropathogenic Escherichia coli
PLoS Pathog.
2007
, vol. 
3
 pg. 
e100
 
9
Wang
H.
Min
G.
Glockshuber
R.
Sun
T.T.
Kong
X.P.
Uropathogenic E. coli adhesin-induced host cell receptor conformational changes: implications in transmembrane signaling transduction
J. Mol. Biol.
2009
, vol. 
392
 (pg. 
352
-
361
)
10
Min
G.
Stolz
M.
Zhou
G.
Liang
F.
Sebbel
P.
Stoffler
D.
Glockshuber
R.
Sun
T.T.
Aebi
U.
Kong
X.P.
Localization of uroplakin Ia, the urothelial receptor for bacterial adhesin FimH, on the six inner domains of the 16 nm urothelial plaque particle
J. Mol. Biol.
2002
, vol. 
317
 (pg. 
697
-
706
)
11
Xie
B.
Zhou
G.
Chan
S.Y.
Shapiro
E.
Kong
X.P.
Wu
X.R.
Sun
T.T.
Costello
C.E.
Distinct glycan structures of uroplakins Ia and Ib: structural basis for the selective binding of FimH adhesin to uroplakin Ia4
J. Biol. Chem.
2006
, vol. 
281
 (pg. 
14644
-
14653
)
12
Wellens
A.
Garofalo
C.
Nguyen
H.
Van Gerven
N.
Slattegard
R.
Hernalsteens
J.P.
Wyns
L.
Oscarson
S.
De Greve
H.
Hultgren
S.
Bouckaert
J.
Intervening with urinary tract infections using anti-adhesives based on the crystal structure of the FimH–oligomannose-3 complex
PLoS ONE
2008
, vol. 
3
 pg. 
e2040
 
13
Hase
K.
Kawano
K.
Nochi
T.
Pontes
G.S.
Fukuda
S.
Ebisawa
M.
Kadokura
K.
Tobe
T.
Fujimura
Y.
Kawano
S.
, et al. 
Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response
Nature
2009
, vol. 
462
 (pg. 
226
-
230
)
14
Carvalho
F.A.
Barnich
N.
Sivignon
A.
Darcha
C.
Chan
C.H.
Stanners
C.P.
Darfeuille-Michaud
A.
Crohn's disease adherent-invasive Escherichia coli colonize and induce strong gut inflammation in transgenic mice expressing human CEACAM
J. Exp. Med.
2009
, vol. 
206
 (pg. 
2179
-
2189
)
15
Bouckaert
J.
Mackenzie
J.
de Paz
J.L.
Chipwaza
B.
Choudhury
D.
Zavialov
A.
Mannerstedt
K.
Anderson
J.
Pierard
D.
Wyns
L.
, et al. 
The affinity of the FimH fimbrial adhesin is receptor-driven and quasi-independent of Escherichia coli pathotypes
Mol. Microbiol.
2006
, vol. 
61
 (pg. 
1556
-
1568
)
16
Chen
S.L.
Hung
C.S.
Pinkner
J.S.
Walker
J.N.
Cusumano
C.K.
Li
Z.
Bouckaert
J.
Gordon
J.I.
Hultgren
S.J.
Positive selection identifies an in vivo role for FimH during urinary tract infection in addition to mannose binding
Proc. Natl. Acad. Sci. U.S.A.
2009
, vol. 
106
 (pg. 
22439
-
22444
)
17
Hung
C.-S.
Bouckaert
J.
Hung
D.L.
Pinkner
J.
Winberg
C.
Defusco
A.
Auguste
C.G.
Strouse
R.
Langermann
S.
Waksman
G.
Hultgren
S.J.
Structural basis of tropism of Escherichia coli to the bladder during urinary tract infection
Mol. Microbiol.
2002
, vol. 
44
 (pg. 
903
-
915
)
18
Geerlings
S.E.
Urinary tract infections in patients with diabetes mellitus: epidemiology, pathogenesis and treatment
Int. J. Antimicrob. Agents
2008
, vol. 
31
 
Suppl. 1
(pg. 
S54
-
S57
)
19
Geerlings
S.E.
Meiland
R.
van Lith
E.C.
Brouwer
E.C.
Gaastra
W.
Hoepelman
A.I.M.
Adherence of type 1-fimbriated Escherichia coli to uroepithelial cells: more in diabetic women than in control subjects
Diabetes Care
2002
, vol. 
25
 (pg. 
1405
-
1409
)
20
Knight
S.D.
Bouckaert
J.
Structure, function, and assembly of type 1 fimbriae
Top. Curr. Chem.
2009
, vol. 
288
 (pg. 
67
-
107
)
21
Reeves
P.J.
Callewaert
N.
Contreras
R.
Khorana
H.G.
Structure and function in rhodopsin: high-level expression of rhodopsin with restricted and homogeneous N-glycosylation by a tetracycline-inducible N-acetylglucosaminyltransferase I-negative HEK293S stable mammalian cell line
Proc. Natl. Acad. Sci. U.S.A.
2002
, vol. 
99
 (pg. 
13419
-
13424
)
22
de Boer
A.R.
Hokke
C.H.
Deelder
A.M.
Wuhrer
M.
General microarray technique for immobilization and screening of natural glycans
Anal. Chem.
2007
, vol. 
79
 (pg. 
8107
-
8113
)
23
Lonardi
E.
Balog
C.I.
Deelder
A.M.
Wuhrer
M.
Natural glycan microarrays
Expert Rev. Proteomics
2010
, vol. 
7
 (pg. 
761
-
774
)
24
Watts
J.C.
Huo
H.
Bai
Y.
Ehsani
S.
Jeon
A.H.
Shi
T.
Daude
N.
Lau
A.
Young
R.
Xu
L.
, et al. 
Interactome analyses identify ties of PrP and its mammalian paralogs to oligomannosidic N-glycans and endoplasmic reticulum-derived chaperones
PLoS Pathog.
2009
, vol. 
5
 pg. 
e1000608
 
25
Lau
K.S.
Partridge
E.A.
Grigorian
A.
Silvescu
C.I.
Reinhold
V.N.
Demetriou
M.
Dennis
J.W.
Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation
Cell
2007
, vol. 
129
 (pg. 
123
-
134
)
26
Dam
T.K.
Brewer
F.C.
Maintenance of cell surface glycan density by lectin–glycan interactions: a homeostatic and innate immune regulatory mechanism
Glycobiology
2010
, vol. 
20
 (pg. 
1061
-
1064
)
27
Eto
D.S.
Mulvey
M.A.
Flushing bacteria out of the bladder
Nat. Med.
2007
, vol. 
13
 (pg. 
531
-
532
)
28
Sharon
N.
Lis
H.
Carbohydrates in cell recognition
Sci. Am.
1993
, vol. 
268
 (pg. 
82
-
89
)
29
Mysorekar
I.U.
Hultgren
S.J.
Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract
Proc. Natl. Acad. Sci. U.S.A.
2006
, vol. 
103
 (pg. 
14170
-
14175
)
30
Eto
D.S.
Sundsbak
J.L.
Mulvey
M.A.
Actin-gated intracellular growth and resurgence of uropathogenic Escherichia coli
Cell. Microbiol.
2006
, vol. 
8
 (pg. 
704
-
717
)
31
Mysorekar
I.U.
Isaacson-Schmid
M.
Walker
J.N.
Mills
J.C.
Hultgren
S.J.
Bone morphogenetic protein 4 signaling regulates epithelial renewal in the urinary tract in response to uropathogenic infection
Cell Host Microbe
2009
, vol. 
5
 (pg. 
463
-
475
)
32
Franz
S.
Herrmann
K.
Furnrohr
B.G.
Sheriff
A.
Frey
B.
Gaipl
U.S.
Voll
R.E.
Kalden
J.R.
Jack
H.M.
Herrmann
M.
After shrinkage apoptotic cells expose internal membrane-derived epitopes on their plasma membranes
Cell Death Differ.
2007
, vol. 
14
 (pg. 
733
-
742
)
33
Bilyy
R.
Kit
Y.
Hellman
U.
Tryndyak
V.
Kaminskyy
V.
Stoika
R.
In vivo expression and characteristics of novel α-D-mannose-rich glycoprotein markers of apoptotic cells
Cell Biol. Int.
2005
, vol. 
29
 (pg. 
920
-
928
)
34
Bilyy
R.
Stoika
R.
Search for novel cell surface markers of apoptotic cells
Autoimmunity
2007
, vol. 
40
 (pg. 
249
-
253
)
35
Meesmann
H.M.
Fehr
E.M.
Kierschke
S.
Herrmann
M.
Bilyy
R.
Heyder
P.
Blank
N.
Krienke
S.
Lorenz
H.M.
Schiller
M.
Decrease of sialic acid residues as an eat-me signal on the surface of apoptotic lymphocytes
J. Cell Sci.
2010
, vol. 
123
 (pg. 
3347
-
3356
)
36
Rosen
D.A.
Hooton
T.M.
Stamm
W.E.
Humphrey
P.A.
Hultgren
S.J.
Detection of intracellular bacterial communities in human urinary tract infection
PLoS Med.
2007
, vol. 
4
 pg. 
e329
 
37
Muenzner
P.
Bachmann
V.
Zimmermann
W.
Hentschel
J.
Hauck
C.R.
Human-restricted bacterial pathogens block shedding of epithelial cells by stimulating integrin activation
Science
2010
, vol. 
329
 (pg. 
1197
-
1201
)
38
Sukumaran
S.K.
Fu
N.Y.
Tin
C.B.
Wan
K.F.
Lee
S.S.
Yu
V.C.
A soluble form of the pilus protein FimA targets the VDAC–hexokinase complex at mitochondria to suppress host cell apoptosis
Mol. Cell
2010
, vol. 
37
 (pg. 
768
-
783
)
39
Vagin
O.
Kraut
J.A.
Sachs
G.
Role of N-glycosylation in trafficking of apical membrane proteins in epithelia
Am. J. Physiol. Renal Physiol.
2009
, vol. 
296
 (pg. 
F459
-
F469
)
40
Ahmad
N.
Gabius
H.J.
Andre
S.
Kaltner
H.
Sabesan
S.
Roy
R.
Liu
B.
Macaluso
F.
Brewer
C.F.
Galectin-3 precipitates as a pentamer with synthetic multivalent carbohydrates and forms heterogeneous cross-linked complexes
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
10841
-
10847
)
41
Vassilopoulos
S.
Esk
C.
Hoshino
S.
Funke
B.H.
Chen
C.Y.
Plocik
A.M.
Wright
W.E.
Kucherlapati
R.
Brodsky
F.M.
A role for the CHC22 clathrin heavy-chain isoform in human glucose metabolism
Science
2009
, vol. 
324
 (pg. 
1192
-
1196
)
42
Tsao
T.S.
Burcelin
R.
Katz
E.B.
Huang
L.
Charron
M.J.
Enhanced insulin action due to targeted GLUT4 overexpression exclusively in muscle
Diabetes
1996
, vol. 
45
 (pg. 
28
-
36
)
43
Kolm-Litty
V.
Sauer
U.
Nerlich
A.
Lehmann
R.
Schleicher
E.D.
High glucose-induced transforming growth factor β1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells
J. Clin. Invest.
1998
, vol. 
101
 (pg. 
160
-
169
)
44
Rosen
D.A.
Hung
C.S.
Kline
K.A.
Hultgren
S.J.
Streptozocin-induced diabetic mouse model of urinary tract infection
Infect. Immun.
2008
, vol. 
76
 (pg. 
4290
-
4298
)
45
Carlson
C.M.
Turpin
E.A.
Moser
L.A.
O'Brien
K.B.
Cline
T.D.
Jones
J.C.
Tumpey
T.M.
Katz
J.M.
Kelley
L.A.
Gauldie
J.
Schultz-Cherry
S.
Transforming growth factor-β: activation by neuraminidase and role in highly pathogenic H5N1 influenza pathogenesis
PLoS Pathog.
2010
, vol. 
6
 pg. 
e1001136
 
46
Chuang
P.Y.
Yu
Q.
Fang
W.
Uribarri
J.
He
J.C.
Advanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factor
Kidney Int.
2007
, vol. 
72
 (pg. 
965
-
976
)