The use of synthetic peptides in the design of a consensus sequence vaccine for Pseudomonas aeruginosa

Cachia, Paul J.; Glasier, L. M. G.; Hodgins, R.R.W.; Wong, Wah Y.; Irvin, Randall T.; Hodges, Robert S.

doi:10.1111/j.1399-3011.1998.tb01243.x

Cited by 35 publications

(14 citation statements)

References 42 publications

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“…To explain how D regions with diverse sequences can provide similar functions, their adhesive properties were attributed to main chain-rather than side chain-based interactions (172). Those data led to a focus on development of anti-P. aeruginosa vaccines containing peptides corresponding to the D region (71,72,75,162,216). Newer information showing that the minor pilins are present in sheared pilus fractions (154,416) and that the orthologous PilC1 or PilC2 (Neisseria and Kingella) and PilY1 (Pseudomonas) proteins are potentially pilus associated and required for adherence to-and manipulation of-the host (174,204,217,288,289,384) suggests that additional studies are needed to unequivocally identify all T4aP adhesins.…”

Section: Figmentioning

confidence: 99%

Type IV Pilin Proteins: Versatile Molecular Modules

Giltner

Nguyen

Burrows

2012

Microbiol Mol Biol Rev

398

519

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SUMMARYType IV pili (T4P) are multifunctional protein fibers produced on the surfaces of a wide variety of bacteria and archaea. The major subunit of T4P is the type IV pilin, and structurally related proteins are found as components of the type II secretion (T2S) system, where they are called pseudopilins; of DNA uptake/competence systems in both Gram-negative and Gram-positive species; and of flagella, pili, and sugar-binding systems in the archaea. This broad distribution of a single protein family implies both a common evolutionary origin and a highly adaptable functional plan. The type IV pilin is a remarkably versatile architectural module that has been adopted widely for a variety of functions, including motility, attachment to chemically diverse surfaces, electrical conductance, acquisition of DNA, and secretion of a broad range of structurally distinct protein substrates. In this review, we consider recent advances in this research area, from structural revelations to insights into diversity, posttranslational modifications, regulation, and function.

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Section: Figmentioning

confidence: 99%

Type IV Pilin Proteins: Versatile Molecular Modules

Giltner

Nguyen

Burrows

2012

Microbiol Mol Biol Rev

398

519

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“…Alteration of the highly conserved C-terminal type II beta turn had marked effects on assembly. This structural feature was the focus in previous studies of pilus-mediated adherence since it is present in peptide mimics reported to bind to abiotic surfaces and host cells and because it forms part of the epitope for antibodies able to block pilus-mediated attachment (9,12,13,25,57). It is possible that alteration of this region affects either the self-interaction of PilA subunits or their interactions with other components of the T4P system that are important for initiation or control of assembly, such as the minor pilins (2,4).…”

mentioning

confidence: 99%

Single-Residue Changes in the C-Terminal Disulfide-Bonded Loop of thePseudomonas aeruginosaType IV Pilin Influence Pilus Assembly and Twitching Motility

et al. 2009

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PilA, the major pilin subunit of Pseudomonas aeruginosa type IV pili (T4P), is a principal structural component. PilA has a conserved C-terminal disulfide-bonded loop (DSL) that has been implicated as the pilus adhesinotope. Structural studies have suggested that DSL is involved in intersubunit interactions within the pilus fiber. PilA mutants with single-residue substitutions, insertions, or deletions in the DSL were tested for pilin stability, pilus assembly, and T4P function. Mutation of either Cys residue of the DSL resulted in pilins that were unable to assemble into fibers. Ala replacements of the intervening residues had a range of effects on assembly or function, as measured by changes in surface pilus expression and twitching motility. Modification of the C-terminal P-X-X-C type II beta-turn motif, which is one of the few highly conserved features in pilins across various species, caused profound defects in assembly and twitching motility. Expression of pilins with suspected assembly defects in a pilA pilT double mutant unable to retract T4P allowed us to verify which subunits were physically unable to assemble. Use of two different PilA antibodies showed that the DSL may be an immunodominant epitope in intact pili compared with pilin monomers. Sequence diversity of the type IVa pilins likely reflects an evolutionary compromise between retention of function and antigenic variation. The consequences of DSL sequence changes should be evaluated in the intact protein since it is technically feasible to generate DSL-mimetic peptides with mutations that will not appear in the natural repertoire due to their deleterious effects on assembly.The gram-negative opportunistic pathogen Pseudomonas aeruginosa uses polar type IV pili (T4P) to attach to various materials, to move across surfaces via twitching motility, and to initiate host colonization and biofilm formation. T4P are widely distributed among bacteria and have been most extensively studied in Neisseria spp., Escherichia coli, Vibrio cholerae, and P. aeruginosa (8,16,42). T4P are divided into two major groups, type IVa and type IVb pili (T4aP and T4bP, respectively); there are several differences that distinguish these subfamilies (reviewed in reference 16). Most P. aeruginosa strains express T4aP composed of one of five different variants of the 15-to 17-kDa PilA protein (37).The crystal structures of N-terminally truncated or fulllength forms of PilA from P. aeruginosa strains PAK and K122-4 have been solved (17,18,28,34), as has the structure of the type IVa pilin from Neisseria gonorrhoeae MS11, called PilE (45). The pilins have a ladle-like structure, with a long, hydrophobic, kinked N-terminal alpha helix joined to a Cterminal domain of antiparallel beta-sheet architecture, terminating in a characteristic disulfide-bonded loop (DSL; also called the D-region). In a recent report describing the cryoelectron microscopy-derived ultrastructure of an assembled type IV pilus from N. gonorrhoeae, Craig and colleagues confirmed the predictions of earlier mo...

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“…98 Consensus synthetic peptide sequences analogous to the receptor binding region of P. aeruginosa pilin have been proposed as immunogens, which could elicit cross-reactive antibodies that would inhibit adherence of a broad range of P. aeruginosa strains. [99][100][101][102][103] These anti-pilus synthetic peptide conjugates also generated higher antibody titers with higher affinity compared with a pilin protein vaccine. …”

Section: Outer Membrane Proteinsmentioning

confidence: 97%