Protein E of<i>Haemophilus influenzae</i>Is a Ubiquitous Highly Conserved Adhesin

Singh, Birendra; Brant, Marta; Kilian, Mogens; Hallström, Björn M.; Riesbeck, Kristian

doi:10.1086/649782

Cited by 33 publications

(35 citation statements)

References 17 publications

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“…Because clinical NTHi isolates express the adhesion protein PE, we hypothesized that PE is a plasminogen-binding protein (21). Consequently, binding of plasminogen to recombinant PE, to the PE knockout strain, and to PE expressed on the surface of E. coli was tested.…”

Section: Discussionmentioning

confidence: 99%

“…Because NTHi 3655 isolates express PE on their surface (21), this bacterial surface and adhesion protein was considered as a candidate ligand for plasminogen. Therefore, binding of plasminogen to recombinant PE was assayed.…”

Section: Pe Is a Plasminogen-binding Protein Of Nthimentioning

confidence: 99%

“…PE mediates adhesion to and activates human epithelial cells. The pe gene is constitutively expressed in NTHi and is highly conserved among clinical NTHi isolates (21). PE uses the central 24-aa-long core domain (i.e., aa 84-108) to contact human epithelial cells and to induce proinflammatory responses.…”

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confidence: 99%

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Haemophilus influenzae Uses the Surface Protein E To Acquire Human Plasminogen and To Evade Innate Immunity

Barthel

Singh

Riesbeck

et al. 2012

The Journal of Immunology

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Pathogenic microbes acquire the human plasma protein plasminogen to their surface. In this article, we characterize binding of this important coagulation regulator to the respiratory pathogen nontypeable Haemophilus influenzae and identify the Haemophilus surface protein E (PE) as a new plasminogen-binding protein. Plasminogen binds dose dependently to intact bacteria and to purified PE. The plasminogen–PE interaction is mediated by lysine residues and is also affected by ionic strength. The H. influenzae PE knockout strain (nontypeable H. influenzae 3655Δpe) bound plasminogen with ∼65% lower intensity as compared with the wild-type, PE-expressing strain. In addition, PE expressed ectopically on the surface of Escherichia coli also bound plasminogen. Plasminogen, either attached to intact H. influenzae or bound to PE, was accessible for urokinase plasminogen activator. The converted active plasmin cleaved the synthetic substrate S-2251, and the natural substrates fibrinogen and C3b. Using synthetic peptides that cover the complete sequence of the PE protein, the major plasminogen-binding region was localized to a linear 28-aa-long N-terminal peptide, which represents aa 41–68. PE binds plasminogen and also vitronectin, and the two human plasma proteins compete for PE binding. Thus, PE is a major plasminogen-binding protein of the Gram-negative bacterium H. influenzae, and when converted to plasmin, PE-bound plasmin aids in immune evasion and contributes to bacterial virulence.

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Section: Discussionmentioning

confidence: 99%

Section: Pe Is a Plasminogen-binding Protein Of Nthimentioning

confidence: 99%

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Haemophilus influenzae Uses the Surface Protein E To Acquire Human Plasminogen and To Evade Innate Immunity

Barthel

Singh

Riesbeck

et al. 2012

The Journal of Immunology

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“…Importantly, immunization with the PE amino acid (aa) 84 to 108 peptide showed significantly better pulmonary clearance in a mouse model than immunization with an unrelated control peptide (12). When the pe gene was sequenced in all Haemophilus spp., including Hib and NTHI clinical isolates, we found that PE is a ubiquitous Haemophilus outer membrane protein (13). The active vitronectin-binding region PE aa 84 to 106 was found to be 100% conserved.…”

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confidence: 85%

The Unique Structure of Haemophilus influenzae Protein E Reveals Multiple Binding Sites for Host Factors

et al. 2013

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cHaemophilus influenzae protein E (PE) is a multifunctional adhesin involved in direct interactions with lung epithelial cells and host proteins, including plasminogen and the extracellular matrix proteins vitronectin and laminin. We recently crystallized PE and successfully collected X-ray diffraction data at 1.8 Å. Here, we solved the structure of a recombinant version of PE and analyzed different functional regions. It is a dimer in solution and in the asymmetric unit of the crystals. The dimer has a structure that resembles a flattened ␤-barrel. It is, however, not a true ␤-barrel, as there are differences in both the hydrogen-bonding pattern and the shape. Each monomer consisted of a 6-stranded antiparallel ␤-sheet with a rigid ␣-helix at the C terminus tethered to the concave side of the sheet by a disulfide bridge. The laminin/plasminogen binding region (residues 41 to 68) is exposed, while the vitronectin binding region (residues 84 to 108) is partially accessible in the dimer. The dimerized PE explains the simultaneous interaction with laminin and vitronectin. In addition, we found this unique adhesin to be present in many bacterial genera of the family Pasteurellaceae and also orthologues in other, unrelated species (Enterobacter cloacae and Listeria monocytogenes). Peptides corresponding to the surface-exposed regions PE 24 to 37, PE 74 to 89, and PE 134 to 156 were immunogenic in the mouse. Importantly, these peptide-based antibodies also recognized PE at the bacterial surface. Taken together, our detailed structure of PE explains how this important virulence factor of H. influenzae simultaneously interacts with host vitronectin, laminin, or plasminogen, promoting bacterial pathogenesis.

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“…influenzae protein E (PE) is a 16 kDa, highly conserved (96.9%-100%), ubiquitous outer membrane lipoprotein that exists in both encapsulated H. influenzae and NTHi (Singh et al, 2010). PE was initially described as an adhesin that binds to epithelial cells of different origins including those from COPD patients (Ronander et al, 2009).…”

Section: Introductionmentioning

confidence: 99%