The Metal Ion-Dependent Adhesion Site Motif of the Enterococcus faecalis EbpA Pilin Mediates Pilus Function in Catheter-Associated Urinary Tract Infection

Nielsen, Hailyn V.; Guiton, Pascale S.; Kline, Kimberly; Port, Gary C.; Pinkner, Jerome S.; Neiers, Fabrice; Normark, Staffan; Henriques‐Normark, Birgitta; Caparon, Michael G.; Hultgren, Scott J.

doi:10.1128/mbio.00177-12

Cited by 131 publications

(180 citation statements)

References 57 publications

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“…Additionally, E. faecalis forms essential interactions with Fg via the pilus tip protein EbpA, which has several features in common with MRSA's ClfB. The ClfB crystal structure has been solved, and molecular modeling of EbpA suggests the protein shares a similar structural organization and maintains an analogous central Fg-binding groove to ClfB (46,57,61). Additionally, both ClfB and EbpA contain a metal iondependent adhesion-site motif, which in ClfB, and likely in EbpA, binds metal cations and coordinates the Fg-binding groove facilitating ligand binding (46,61).…”

Section: Discussionmentioning

confidence: 99%

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Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

Walker

Flores-Mireles

Pinkner

et al. 2017

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

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103

164

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Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of catheter-associated urinary tract infection (CAUTI), which frequently progresses to more serious invasive infections. We adapted a mouse model of CAUTI to investigate how catheterization increases an individual's susceptibility to MRSA UTI. This analysis revealed that catheterization was required for MRSA to achieve high-level, persistent infection in the bladder. As shown previously, catheter placement induced an inflammatory response resulting in the release of the host protein fibrinogen (Fg), which coated the bladder and implant. Following infection, we showed that MRSA attached to the urothelium and implant in patterns that colocalized with deposited Fg. Furthermore, MRSA exacerbated the host inflammatory response to stimulate the additional release and accumulation of Fg in the urinary tract, which facilitated MRSA colonization. Consistent with this model, analysis of catheters from patients with S. aureus-positive cultures revealed colocalization of Fg, which was deposited on the catheter, with S. aureus. Clumping Factors A and B (ClfA and ClfB) have been shown to contribute to MRSA-Fg interactions in other models of disease. We found that mutants in clfA had significantly greater Fg-binding defects than mutants in clfB in several in vitro assays. Paradoxically, only the ClfB − strain was significantly attenuated in the CAUTI model. Together, these data suggest that catheterization alters the urinary tract environment to promote MRSA CAUTI pathogenesis by inducing the release of Fg, which the pathogen enhances to persist in the urinary tract despite the host's robust immune response.host-pathogen interactions | MRSA CAUTI | ClfB-fibrinogen interactions

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Section: Discussionmentioning

confidence: 99%

“…Our previous reports show that E. faecalis shares several common features with MRSA during CAUTI (26,(36)(37)(38)57). First, both E. faecalis and MRSA cause persistent disease by overcoming the inflammation induced upon implant placement, which consists of the recruitment of immune cells, including activated macrophages and neutrophils (37).…”

Section: Discussionmentioning

confidence: 99%

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

Walker

Flores-Mireles

Pinkner

et al. 2017

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

Self Cite

103

164

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“…Well-studied examples of VWA domains occur in some integrins, extracellular matrix proteins, and magnesium chelatases and perform diverse functions, usually for protein-protein interaction or cell adhesion (Whittaker and Hynes 2002). In bacteria, VWA-containing proteins at the tips of fimbrial fibers in a few gram-positive pathogenic bacteria have been reported to play important roles in host-cell adhesion (Konto-Ghiorghi et al 2009;Nielsen et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Role of Mfa5 in Expression of Mfa1 Fimbriae in Porphyromonas gingivalis

et al. 2016

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Fimbriae are protein-based filamentous appendages that protrude from the bacterial cell surface and facilitate host adhesion. Two types of fimbriae, FimA and Mfa1, of the periodontal pathogen Porphyromonas gingivalis are responsible for adherence to other bacteria and to host cells in the oral cavity. Both fimbrial forms are composed of 5 proteins, but there is limited information about their polymerization mechanisms. Here, the authors evaluated the function of Mfa5, one of the Mfa1 fimbrial accessory proteins. Using mfa5 gene disruption and complementation studies, the authors revealed that Mfa5 affects the incorporation of other accessory proteins, Mfa3 and Mfa4, into fibers and the expression of fimbriae on the cell surface. Mfa5 is predicted to have a C-terminal domain (CTD) that uses the type IX secretion system (T9SS), which is limited to this organism and related Bacteroidetes species, for translocation across the outer membrane. To determine the relationship between the putative Mfa5 CTD and the T9SS, mutants were constructed with in-frame deletion of the CTD and deletion of porU, a C-terminal signal peptidase linked to T9SS-mediated secretion. The ∆CTD-expressing strain presented a similar phenotype to the mfa5 disruption mutant with reduced expression of fimbriae lacking all accessory proteins. The ∆porU mutants and the ∆CTD-expressing strain showed intracellular accumulation of Mfa5. These results indicate that Mfa5 function requires T9SS-mediated translocation across the outer membrane, which is dependent on the CTD, and subsequent incorporation into fibers. These findings suggest the presence of a novel polymerization mechanism of the P. gingivalis fimbriae.

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“…Accumulation of fibrinogen on the urinary catheter provides a surface for the attachment of E. faecalis, which is mediated by the Ebp pilus and involves direct recognition of fibrinogen (82). Deletion of the pilus operon eliminates the ability of the bacteria to adhere to the catheter in vivo and abolishes the infection, demonstrating the essential role for the pilus in mediating attachment to the catheter and establishing disease (82,83).…”

Section: Role Of Ebp Pilus In Enterococcus Catheter-associated Uti (Cmentioning

confidence: 99%

“…Similar to Gram-negative bacteria, minor subunits can be commonly found at the distal end of Gram-positive pili, including adhesins that mediate interactions with host receptors (79). Since their identification nearly 50 years ago, pili have been identified and implicated in diseases for several Gram-positive pathogens including Streptococcus agalactiae (80), Streptococcus pneumonia (81), and Enterococcus faecalis (82,83).…”

Section: Gram-positive Pilimentioning

confidence: 99%

Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

2016

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Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies.

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The Metal Ion-Dependent Adhesion Site Motif of the Enterococcus faecalis EbpA Pilin Mediates Pilus Function in Catheter-Associated Urinary Tract Infection

Cited by 131 publications

References 57 publications

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

Role of Mfa5 in Expression of Mfa1 Fimbriae in Porphyromonas gingivalis

Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

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