Virulent
            <i>Pseudomonas aeruginosa</i>
            infection converts antimicrobial amyloids into cytotoxic prions

Voth, S.B.; Gwin, M.S.; Francis, C.M.; Balczon, Ron; Frank, Dara W.; Pittet, Jean–François; Wagener, Brant M.; Moser, Stephen A.; Alexeyev, Mikhail; Housley, Nicole A.; Audia, Jonathon P.; Piechocki, Scott; Madera, Kayla; Simmons, Autumn; Crawford, Michaela; Stevens, Troy

doi:10.1096/fj.202000051rrr

Cited by 27 publications

(48 citation statements)

References 89 publications

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“…In turn, the present study identified amyloidogenic sequences of the S1 protein from P. aeruginosa that can be used to create antimicrobial peptides capable of targeting antibiotic-resistant strains of this pathogen. Such antimicrobial peptides containing amyloidogenic regions and acting by the mechanism of directed coaggregation with the ribosomal S1 protein may be a promising variant of a new type of antibiotics directed against microorganisms that cause nosocomial and other types of infections [ 67 , 68 , 69 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Amyloidogenic Regions in Pseudomonas aeruginosa Ribosomal S1 Protein

Grishin

Dzhus

Glukhov

et al. 2021

IJMS

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Bacterial S1 protein is a functionally important ribosomal protein. It is a part of the 30S ribosomal subunit and is also able to interact with mRNA and tmRNA. An important feature of the S1 protein family is a strong tendency towards aggregation. To study the amyloidogenic properties of S1, we isolated and purified the recombinant ribosomal S1 protein of Pseudomonas aeruginosa. Using the FoldAmyloid, Waltz, Pasta 2.0, and AGGRESCAN programs, amyloidogenic regions of the protein were predicted, which play a key role in its aggregation. The method of limited proteolysis in combination with high performance liquid chromatography and mass spectrometric analysis of the products, made it possible to identify regions of the S1 protein from P. aeruginosa that are protected from the action of proteinase K, trypsin, and chymotrypsin. Sequences of theoretically predicted and experimentally identified amyloidogenic regions were used to synthesize four peptides, three of which demonstrated the ability to form amyloid-like fibrils, as shown by electron microscopy and fluorescence spectroscopy. The identified amyloidogenic sites can further serve as a basis for the development of new antibacterial peptides against the pathogenic microorganism P. aeruginosa.

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Section: Discussionmentioning

confidence: 99%

Identification of Amyloidogenic Regions in Pseudomonas aeruginosa Ribosomal S1 Protein

Grishin

Dzhus

Glukhov

et al. 2021

IJMS

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“…8), with cystatin C binding to lower molecular weight forms secreted from uninfected cells while being associated with higher molecular weight complexes released from PA103 infected cells. A potential explanation for this varied binding response is provided by our recent studies which demonstrated that infection regulates the type of amyloid secreted from PMVECs [39]. Infection by strains of P. aeruginosa that lack a functional type III secretion system or produce catalytically inactive effector exoenzymes leads to the release of noncytotoxic forms of Aβ whereas infection with strains that contain functional type III secretion system and active effector enzymes leads to the conversion of Aβ into cytotoxic forms.…”

Section: Discussionmentioning

confidence: 99%

“…A third possibility is that binding of cystatin C to Ab is an adaptive mechanism of the bacterial cells and assists them with avoiding the innate immune response of the cells. Recent data indicate that beta amyloid oligomers are anti-bacterial in nature [37][38][39]. During evolution, the bacteria may have developed a system where they target cystatin C and induce its dimerization so that it inhibits assembly of beta amyloid into an anti-bacterial species.…”

Section: Hbss Pa103mentioning

confidence: 99%

Cystatin C regulates the cytotoxicity of infection‐induced endothelial‐derived β‐amyloid

et al. 2020

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“…Curli is capable of cross-seeding Aβ fibrillation, and treatment of S. Typhimurium with Denantiomeric peptides, known to inhibit Aβ fibrillation, inhibits curli fibrillation and reduces biofilm formation (121). Infection of pulmonary microvascular endothelial cells with clinical P. aeruginosa, which produce the bacterial amyloid FapC, induces production of Aβ and tau, capable of prion-like propagation to naïve cells (145). Evidence from animal models will be required to determine whether bacterial amyloids are capable of directly seeding Aβ or tau aggregation in a manner relevant to neurodegeneration.…”

Section: Neurological Diseasesmentioning

confidence: 99%

Microbiome or Infections: Amyloid-Containing Biofilms as a Trigger for Complex Human Diseases

et al. 2021

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The human microbiota is the community of microorganisms that live upon or within their human host. The microbiota consists of various microorganisms including bacteria, fungi, viruses, and archaea; the gut microbiota is comprised mostly of bacteria. Many bacterial species within the gut microbiome grow as biofilms, which are multicellular communities embedded in an extracellular matrix. Studies have shown that the relative abundances of bacterial species, and therefore biofilms and bacterial byproducts, change during progression of a variety of human diseases including gastrointestinal, autoimmune, neurodegenerative, and cancer. Studies have shown the location and proximity of the biofilms within the gastrointestinal tract might impact disease outcome. Gram-negative enteric bacteria secrete the amyloid curli, which makes up as much as 85% of the extracellular matrix of enteric biofilms. Curli mediates cell-cell attachment and attachment to various surfaces including extracellular matrix components such as fibronectin and laminin. Structurally, curli is strikingly similar to pathological and immunomodulatory human amyloids such as amyloid-β, which has been implicated in Alzheimer's disease, α-synuclein, which is involved in Parkinson's disease, and serum amyloid A, which is secreted during the acute phase of inflammation. The immune system recognizes both bacterial amyloid curli and human amyloids utilizing the same receptors, so curli also induces inflammation. Moreover, recent work indicates that curli can participate in the self-assembly process of pathological human amyloids. Curli is found within biofilms of commensal enteric bacteria as well as invasive pathogens; therefore, evidence suggests that curli contributes to complex human diseases. In this review, we summarize the recent findings on how bacterial biofilms containing curli participate in the pathological and immunological processes in gastrointestinal diseases, systemic autoimmune diseases, and neurodegenerative diseases.

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Virulent Pseudomonas aeruginosa infection converts antimicrobial amyloids into cytotoxic prions

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 27 publications

References 89 publications

Identification of Amyloidogenic Regions in Pseudomonas aeruginosa Ribosomal S1 Protein

Identification of Amyloidogenic Regions in Pseudomonas aeruginosa Ribosomal S1 Protein

Cystatin C regulates the cytotoxicity of infection‐induced endothelial‐derived β‐amyloid

Microbiome or Infections: Amyloid-Containing Biofilms as a Trigger for Complex Human Diseases

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