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New Insights into Proteases and Chaperones in Pathogenic Microorganisms

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Special Issue Information
Keywords
Published Papers

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 13161

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Special Issue Editors

Prof. Dr. Joanna Skórko-Glonek

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Guest Editor

Department of General and Medical Biochemistry, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
Interests: proteases; chaperones; protein quality control; structure function dependence; regulation of enzymatic activity; stress response; virulence factors

Prof. Dr. Silja Wessler

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Co-Guest Editor

Department of Molecular Biology, Division of Microbiology, Paris-Lodron University of Salzburg, Billroth Str. 11, A-5020 Salzburg, Austria
Interests: Helicobacter pylori; host-pathogen interactions; pathogenic factors; signal transduction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

To infect the host and establish infections, pathogenic microorganisms must cross the host’s protective barriers, overcome defence mechanisms and finally find a suitable niche, using a wide range of virulence factors. Moreover, at all the stages of infection, pathogens are exposed to various stressors, whose actions may damage the pathogen’s macromolecules, including proteins. To counteract the effects of stress, pathogens induce dedicated response mechanisms, including the increased synthesis of components of the protein quality-control system.

Proteases and chaperones are important at all stages of infection, acting in both virulence and protein quality control. These proteins frequently cooperate to facilitate the proper folding and maturation of proteins, including several key virulence factors. Moreover, many secreted proteases are virulence factors themselves. In numerous cases, the roles of proteases and chaperones are so important that a lack of their activity leads to the pathogen’s cell death or virulence attenuation. For these reasons, proteases and chaperones directly involved in the pathogenesis of microbial infections are considered attractive therapeutic targets in the development of antimicrobials as alternatives to conventional antibiotics or to support antibiotic therapy.

The aim of this Special Issue is to collect recent findings that characterize proteases and/or chaperones that are involved in processes related to the pathogenic lifestyles of microorganisms. Publications addressing the development of antimicrobials that modulate the function/activity of proteases and chaperones are also welcome.

I look forward to receiving your contributions.

Prof. Dr. Joanna Skórko-Glonek
Prof. Dr. Silja Wessler
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Protease
Chaperone
Virulence factor
Virulence determinant
Protein maturation
Folding and secretion
Pathogen dissemination
Nutrient acquisition
Degradation of extracellular matrix
Cell junction damage
Protease inhibitors
Antimicrobials

Published Papers (4 papers)

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Research

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14 pages, 6832 KiB

Open AccessArticle

Campylobacter jejuni Serine Protease HtrA Induces Paracellular Transmigration of Microbiota across Polarized Intestinal Epithelial Cells

by Irshad Sharafutdinov, Nicole Tegtmeyer, Mathias Müsken and Steffen Backert

Biomolecules 2022, 12(4), 521; https://doi.org/10.3390/biom12040521 - 30 Mar 2022

Cited by 8 | Viewed by 2772

Abstract

Campylobacter jejuni represents an eminent zoonotic germ responsible for foodborne infections causing campylobacteriosis. In addition, infections with C. jejuni constitute a risk factor for the occurrence of inflammatory bowel disease (IBD). In the latter case, patients show inflammatory reactions not only against C. jejuni, but also against the non-infectious microbiota. However, the involved mechanisms and molecular basis are still largely unclear. We recently reported that C. jejuni breaches the intestinal epithelial barrier by secretion of serine protease HtrA (high temperature requirement A), which cleaves several major tight and adherens junction proteins. In the present study, we aimed to study if HtrA-expressing C. jejuni may also trigger the transepithelial migration of non-pathogenic gastrointestinal microbiota. Using confocal immunofluorescence and scanning electron microscopy, we demonstrate that C. jejuni wild-type (wt) as well as the isogenic ∆htrA mutant bind to the surface of polarized intestinal Caco-2 epithelial cells, but do not invade them at the apical side. Instead, C. jejuni wt, but not ∆htrA mutant, disrupt the cellular junctions and transmigrate using the paracellular route between neighboring cells. Using transwell filter systems, we then co-incubated the cells with C. jejuni and non-invasive microbiota strains, either Escherichia coli or Lactococcus lactis. Interestingly, C. jejuni wt, but not ∆htrA mutant, induced the efficient transmigration of these microbiota bacteria into the basal compartment. Thus, infection of the intestinal epithelium with C. jejuni causes local opening of cellular junctions and paracellular translocation in an HtrA-dependent manner, which paves the way for transmigration of microbiota that is otherwise non-invasive. Taken together, these findings may have impacts on various Campylobacter-associated diseases such as IBD, which are discussed here. Full article

(This article belongs to the Special Issue New Insights into Proteases and Chaperones in Pathogenic Microorganisms)

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13 pages, 2063 KiB

Open AccessCommunication

E-Cadherin Orthologues as Substrates for the Serine Protease High Temperature Requirement A (HtrA)

by Sabine Bernegger, Evelyn Hutterer, Urszula Zarzecka, Thomas P. Schmidt, Markus Huemer, Isabella Widlroither, Gernot Posselt, Joanna Skorko-Glonek and Silja Wessler

Biomolecules 2022, 12(3), 356; https://doi.org/10.3390/biom12030356 - 24 Feb 2022

Cited by 1 | Viewed by 1975

Abstract

Helicobacter pylori (H. pylori) expresses the serine protease and chaperone High temperature requirement A (HtrA) that is involved in periplasmic unfolded protein stress response. Additionally, H. pylori-secreted HtrA directly cleaves the human cell adhesion molecule E-cadherin leading to a local disruption of intercellular adhesions during pathogenesis. HtrA-mediated E-cadherin cleavage has been observed in response to a broad range of pathogens, implying that it is a prevalent mechanism in humans. However, less is known whether E-cadherin orthologues serve as substrates for bacterial HtrA. Here, we compared HtrA-mediated cleavage of human E-cadherin with murine, canine, and simian E-cadherin in vitro and during bacterial infection. We found that HtrA targeted mouse and dog E-cadherin equally well, whereas macaque E-cadherin was less fragmented in vitro. We stably re-expressed orthologous E-cadherin (Cdh1) in a CRISPR/Cas9-mediated cdh1 knockout cell line to investigate E-cadherin shedding upon infection using H. pylori wildtype, an isogenic htrA deletion mutant, or complemented mutants as bacterial paradigms. In Western blot analyses and super-resolution microscopy, we demonstrated that H. pylori efficiently cleaved E-cadherin orthologues in an HtrA-dependent manner. These data extend previous knowledge to HtrA-mediated E-cadherin release in mammals, which may shed new light on bacterial infections in non-human organisms. Full article

(This article belongs to the Special Issue New Insights into Proteases and Chaperones in Pathogenic Microorganisms)

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18 pages, 31759 KiB

Open AccessArticle

Feeling the Heat: The Campylobacter jejuni HrcA Transcriptional Repressor Is an Intrinsic Protein Thermosensor

by Giovanni Versace, Marta Palombo, Anna Menon, Vincenzo Scarlato and Davide Roncarati

Biomolecules 2021, 11(10), 1413; https://doi.org/10.3390/biom11101413 - 27 Sep 2021

Cited by 4 | Viewed by 2468

Abstract

The heat-shock response, a universal protective mechanism consisting of a transcriptional reprogramming of the cellular transcriptome, results in the accumulation of proteins which counteract the deleterious effects of heat-stress on cellular polypeptides. To quickly respond to thermal stress and trigger the heat-shock response, bacteria rely on different mechanisms to detect temperature variations, which can involve nearly all classes of biological molecules. In Campylobacter jejuni the response to heat-shock is transcriptionally controlled by a regulatory circuit involving two repressors, HspR and HrcA. In the present work we show that the heat-shock repressor HrcA acts as an intrinsic protein thermometer. We report that a temperature upshift up to 42 °C negatively affects HrcA DNA-binding activity to a target promoter, a condition required for de-repression of regulated genes. Furthermore, we show that this impairment of HrcA binding at 42 °C is irreversible in vitro, as DNA-binding was still not restored by reversing the incubation temperature to 37 °C. On the other hand, we demonstrate that the DNA-binding activity of HspR, which controls, in combination with HrcA, the transcription of chaperones’ genes, is unaffected by heat-stress up to 45 °C, portraying this master repressor as a rather stable protein. Additionally, we show that HrcA binding activity is enhanced by the chaperonin GroE, upon direct protein–protein interaction. In conclusion, the results presented in this work establish HrcA as a novel example of intrinsic heat-sensing transcriptional regulator, whose DNA-binding activity is positively modulated by the GroE chaperonin. Full article

(This article belongs to the Special Issue New Insights into Proteases and Chaperones in Pathogenic Microorganisms)

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Review

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19 pages, 1166 KiB

Open AccessEditor’s ChoiceReview

An Introduction to Bacterial Biofilms and Their Proteases, and Their Roles in Host Infection and Immune Evasion

by Juan Sebastián Ramírez-Larrota and Ulrich Eckhard

Biomolecules 2022, 12(2), 306; https://doi.org/10.3390/biom12020306 - 14 Feb 2022

Cited by 21 | Viewed by 4687

Abstract

Bacterial biofilms represent multicellular communities embedded in a matrix of extracellular polymeric substances, conveying increased resistance against environmental stress factors but also antibiotics. They are shaped by secreted enzymes such as proteases, which can aid pathogenicity by degrading host proteins of the connective tissue or the immune system. Importantly, both secreted proteases and the capability of biofilm formation are considered key virulence factors. In this review, we focus on the basic aspects of proteolysis and protein secretion, and highlight various secreted bacterial proteases involved in biofilm establishment and dispersal, and how they aid bacteria in immune evasion by degrading immunoglobulins and components of the complement system. Thus, secreted proteases represent not only prominent antimicrobial targets but also enzymes that can be used for dedicated applications in biotechnology and biomedicine, including their use as laundry detergents, in mass spectrometry for the glycoprofiling of antibodies, and the desensitization of donor organs intended for positive crossmatch patients. Full article

(This article belongs to the Special Issue New Insights into Proteases and Chaperones in Pathogenic Microorganisms)

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