Prevention of Mucosal
            <i>Escherichia coli</i>
            Infection by FimH-Adhesin-Based Systemic Vaccination

Langermann, Solomon; Palaszynski, Susan R.; Barnhart, Michelle M.; Auguste, Gale; Pinkner, Jerome S.; Burlein, Jeanne E.; Barren, Philip; Koenig, Scott; Leath, Simon; Jones, C. Hal; Hultgren, Scott J.

doi:10.1126/science.276.5312.607

Cited by 531 publications

(465 citation statements)

References 51 publications

Supporting

Mentioning

448

Contrasting

Unclassified

Order By: Relevance

“…Both of these strains express filamentous adhesive organelles called type 1 pili (Blomfield et al, 1991;Langermann et al, 1997). These fibers mediate both bacterial adherence to and invasion of host epithelial cells, and they are major virulence factors encoded by virtually all UPEC isolates (Martinez et al, 2000).…”

Section: Upec Stimulates Dephosphorylation Of Akt In Bladder Epithelimentioning

confidence: 99%

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

Wiles

Dhakal

Eto

et al. 2008

MBoC

102

View full text Add to dashboard Cite

Uropathogenic Escherichia coli (UPEC) are the major cause of urinary tract infections (UTIs), and they have the capacity to induce the death and exfoliation of target uroepithelial cells. This process can be facilitated by the pore-forming toxin ␣-hemolysin (HlyA), which is expressed and secreted by many UPEC isolates. Here, we demonstrate that HlyA can potently inhibit activation of Akt (protein kinase B), a key regulator of host cell survival, inflammatory responses, proliferation, and metabolism. HlyA ablates Akt activation via an extracellular calcium-dependent, potassium-independent process requiring HlyA insertion into the host plasma membrane and subsequent pore formation. Inhibitor studies indicate that Akt inactivation by HlyA involves aberrant stimulation of host protein phosphatases. We found that two other bacterial pore-forming toxins (aerolysin from Aeromonas species and ␣-toxin from Staphylococcus aureus) can also markedly attenuate Akt activation in a dose-dependent manner. These data suggest a novel mechanism by which sublytic concentrations of HlyA and other pore-forming toxins can modulate host cell survival and inflammatory pathways during the course of a bacterial infection. INTRODUCTIONStrains of uropathogenic Escherichia coli (UPEC) are the leading cause of urinary tract infections (UTIs), which currently rank among the most common of infectious diseases worldwide (Foxman, 2003;Marrs et al., 2005). During the course of an infection, UPEC can stimulate a number of antimicrobial, proinflammatory, prodifferentiation, proliferation, and host cell death pathways (Mulvey, 2002;Mysorekar et al., 2002). In some cases, UPEC can reportedly modulate these signaling events, causing attenuation of host inflammatory responses and potentiating host apoptotic cascades (Klumpp et al., 2001(Klumpp et al., , 2006Hunstad et al., 2005;Billips et al., 2007). These phenomena have been linked in part to the suppression of nuclear factor-B (NF B) activation and downstream signaling by unknown factors associated with UPEC (Klumpp et al., 2001;Hunstad et al., 2005). By hindering host cytokine expression and ensuing inflammatory responses, UPEC may be better able to establish itself and multiply within the cells and tissues of the urinary tract. At the same time, UPEC-induced death of bladder and renal epithelial cells can compromise mucosal barriers, and it may thereby facilitate bacterial dissemination and persistence within the urinary tract (Mulvey et al., 1998Chen et al., 2003a;Bower et al., 2005;Eto et al., 2006;Mansson et al., 2007b).A key regulator of host cell survival pathways is Akt (also known as protein kinase B, PKB; for recent reviews, see Fayard et al., 2005;Song et al., 2005;Manning and Cantley, 2007). This serine/threonine kinase is able to inhibit apoptosis, and it can help control cell cycle and metabolic pathways, endocytosis and vesicular trafficking, and host inflammatory responses, including the activation of NF B. Akt is activated downstream of phosphoinositide 3-kinase (PI3-kinase), which it...

show abstract

Section: Upec Stimulates Dephosphorylation Of Akt In Bladder Epithelimentioning

confidence: 99%

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

Wiles

Dhakal

Eto

et al. 2008

MBoC

102

View full text Add to dashboard Cite

show abstract

“…Although the role of type 1 fimbriate E. coli in the intestinal tract is poorly defined, the adhesin is a virulence factor in urinary tract infections (2)(3)(4)(5)(6)(7). Type 1 fimbriae are proinflammatory, stimulating release of IL-6, IL-8, and tumor necrosis factor ␣, and they act synergistically with other bacterial products such as lipopolysaccharide (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Integrated regulatory responses of fimB to N -acetylneuraminic (sialic) acid and GlcNAc in Escherichia coli K-12

Sohanpal

El-Labany

Lahooti

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

101

132

View full text Add to dashboard Cite

. Here, we show that whereas NanR, a sialic acid-response regulator, binds to region 1, NagC, a GlcNAc-6P-responsive protein, binds to region 2 instead. The NanR-and NagC-binding sites lie adjacent to deoxyadenosine methylase (Dam) methylation sites (5 -GATC) that are protected from modification, and the two regulators are shown to be required for methylation protection at regions 1 and 2, respectively. Mutations in nanR and nagC diminish fimB expression, and both fimB expression and FimB recombination are inhibited by GlcNAc (3-and >35-fold, respectively). Sialic acid catabolism generates GlcNAc-6-P, and whereas GlcNAc disrupts methylation protection by NagC alone, Neu5Ac inhibits the protection mediated by both NanR and NagC as expected. Type 1 fimbriae are proinflammatory, and host defenses enhance the release of both Neu5Ac and GlcNAc by a variety of mechanisms. Inhibition of type 1 fimbriation by these amino sugars may thus help balance the interaction between E. coli and its hosts. type 1 fimbriae

show abstract

“…13,14 but these are targeting type 1 ®mbriated E. coli, and only two out of 15 patients here were infected with this organism, thereby illustrating one disadvantage with the vaccine approach. Also, it is doubtful whether a vaccine can detach already adherent bacteria, while perhaps functional food components in urine can alter the surface interface to allow this to happen.…”

Section: Discussionmentioning

confidence: 94%

Cranberry juice consumption may reduce biofilms on uroepithelial cells: pilot study in spinal cord injured patients

et al. 2001

View full text Add to dashboard Cite

Prevention of Mucosal Escherichia coli Infection by FimH-Adhesin-Based Systemic Vaccination

Cited by 531 publications

References 51 publications

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

Integrated regulatory responses of fimB to N -acetylneuraminic (sialic) acid and GlcNAc in Escherichia coli K-12

Cranberry juice consumption may reduce biofilms on uroepithelial cells: pilot study in spinal cord injured patients

Contact Info

Product

Resources

About