المؤلفون: Rapsinski, Glenn J., Michaels, Lia A., Hill, Madison, Yarrington, Kaitlin D., Haas, Allison L., D'Amico, Emily J., Armbruster, Catherine R., Zemke, Anna, Limoli, Dominique, Bomberger, Jennifer M.

المصدر: PLoS Pathogens; 5/31/2024, Vol. 20 Issue 5, p1-25, 25p

مصطلحات موضوعية: QUORUM sensing, POTASSIUM channels, OPERONS, PSEUDOMONAS aeruginosa, BIOFILMS, POTASSIUM, BACTERIAL adhesion, BACTERIAL proteins

مستخلص: Mucosa-associated biofilms are associated with many human disease states, but the host mechanisms promoting biofilm remain unclear. In chronic respiratory diseases like cystic fibrosis (CF), Pseudomonas aeruginosa establishes chronic infection through biofilm formation. P. aeruginosa can be attracted to interspecies biofilms through potassium currents emanating from the biofilms. We hypothesized that P. aeruginosa could, similarly, sense and respond to the potassium efflux from human airway epithelial cells (AECs) to promote biofilm. Using respiratory epithelial co-culture biofilm imaging assays of P. aeruginosa grown in association with CF bronchial epithelial cells (CFBE41o^-), we found that P. aeruginosa biofilm was increased by potassium efflux from AECs, as examined by potentiating large conductance potassium channel, BKCa (NS19504) potassium efflux. This phenotype is driven by increased bacterial attachment and increased coalescence of bacteria into aggregates. Conversely, biofilm formation was reduced when AECs were treated with a BKCa blocker (paxilline). Using an agar-based macroscopic chemotaxis assay, we determined that P. aeruginosa chemotaxes toward potassium and screened transposon mutants to discover that disruption of the high-sensitivity potassium transporter, KdpFABC, and the two-component potassium sensing system, KdpDE, reduces P. aeruginosa potassium chemotaxis. In respiratory epithelial co-culture biofilm imaging assays, a KdpFABCDE deficient P. aeruginosa strain demonstrated reduced biofilm growth in association with AECs while maintaining biofilm formation on abiotic surfaces. Furthermore, we determined that the Kdp operon is expressed in vivo in people with CF and the genes are conserved in CF isolates. Collectively, these data suggest that P. aeruginosa biofilm formation can be increased by attracting bacteria to the mucosal surface and enhancing coalescence into microcolonies through aberrant AEC potassium efflux sensed by the KdpFABCDE system. These findings suggest host electrochemical signaling can enhance biofilm, a novel host-pathogen interaction, and potassium flux could be a therapeutic target to prevent chronic infections in diseases with mucosa-associated biofilms, like CF. Author summary: Biofilm formation is important for Pseudomonas aeruginosa to cause chronic infections on epithelial surfaces during respiratory diseases, like cystic fibrosis (CF). The host factors that promote biofilm formation on host surfaces are not yet fully understood. Potassium signals from biofilms can attract P. aeruginosa, but it is unknown if potassium from the human cells can influence P. aeruginosa biofilm formation on a host surface. We found that P. aeruginosa biofilm formation on human airway cells can be increased by the potassium currents from airway cells. Furthermore, we determined bacterial genes related to potassium uptake and sensing that contribute to biofilm formation on airway cells, which are expressed in humans during infection. These findings suggest that P. aeruginosa can respond to host potassium signals by forming increased biofilm and that reducing chronic infections may be accomplished by reducing potassium coming from airway cells or blocking the bacterial proteins responsible for the biofilm enhancement by potassium currents. [ABSTRACT FROM AUTHOR]

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المؤلفون: Jean-François Eléouët, Ralph A. Schmid, Quentin Haas, Artur Summerfield, Kemal Mehinagic, Beatrice Zumkehr, Sean R R Hall, Nicolas Ruggli, B. Oliveira Esteves, Melanie Brügger, Marie-Anne Rameix-Welti, Thomas Démoulins, Thomas M. Marti, Ueli Moehrlen, Horst Posthaus, A. Schogler, G. T. Barut, Marco P. Alves

المساهمون: Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Bern, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University Children’s Hospital Zurich, Bern University Hospital [Berne] (Inselspital), Gillies McIndoe Research Institute (GMRI), Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF: 310030_172895 Gottfried und Julia Bangerter-Rhyner-Stiftung, This work acknowledges support from the Swiss National Science Foundation to MPA (www.snf.ch, project 310030_172895), that included partial salary support for MB and TD. This work was also supported by a grant from the Gottfried and Julia Bangerter-Rhyner Foundation to MPA (www.bangerter-stiftung.ch), that included partial salary support to MB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., HAL UVSQ, Équipe, University of Zurich, Alves, Marco P

المصدر: PLoS Pathogens
PLoS Pathogens, Public Library of Science, 2021, 17 (7), pp.e1009789. ⟨10.1371/journal.ppat.1009789⟩
PLoS Pathogens, Public Library of Science, 2021, 17 (7), pp.1-28. ⟨10.1371/journal.ppat.1009789⟩
PLoS Pathogens, 2021, 17 (7), pp.1-28. ⟨10.1371/journal.ppat.1009789⟩
PLoS Pathogens, Vol 17, Iss 7, p e1009789 (2021)
Brügger, Melanie; Démoulins, Thomas; Barut, G. Tuba; Zumkehr, Beatrice; Oliveira Esteves, Blandina I.; Mehinagic, Kemal; Haas, Quentin; Schögler, Aline; Rameix-Welti, Marie-Anne; Eléouët, Jean-François; Moehrlen, Ueli; Marti, Thomas M.; Schmid, Ralph A.; Summerfield, Artur; Posthaus, Horst; Ruggli, Nicolas; Hall, Sean R. R.; Alves, Marco P. (2021). Pulmonary mesenchymal stem cells are engaged in distinct steps of host response to respiratory syncytial virus infection. PLoS pathogens, 17(7), e1009789. Public Library of Science 10.1371/journal.ppat.1009789 <http://dx.doi.org/10.1371/journal.ppat.1009789>

مصطلحات موضوعية: Pulmonology, Angiogenesis, Physiology, [SDV]Life Sciences [q-bio], 2405 Parasitology, Pediatrics, 0302 clinical medicine, Medical Conditions, Animal Cells, Immune Physiology, Medicine and Health Sciences, Respiratory system, Biology (General), Lung, 0303 health sciences, Innate Immune System, 630 Agriculture, Stem Cells, 2404 Microbiology, Cell Differentiation, respiratory system, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, 030220 oncology & carcinogenesis, Cytokines, Cellular Types, Pediatric Infections, Research Article, Stromal cell, QH301-705.5, T cell, Immunology, Acute Lung Injury, 610 Medicine & health, Respiratory Syncytial Virus Infections, Lung injury, Biology, Virus, 03 medical and health sciences, Respiratory Disorders, 1311 Genetics, medicine, 1312 Molecular Biology, Animals, Humans, 10220 Clinic for Surgery, Respiratory Physiology, 030304 developmental biology, 2403 Immunology, Sheep, Regeneration (biology), Mesenchymal stem cell, Biology and Life Sciences, Mesenchymal Stem Cells, Convalescence, Cell Biology, RC581-607, Molecular Development, Health Care, Immune System, Respiratory Syncytial Virus, Human, Respiratory Infections, 2406 Virology, Immunologic diseases. Allergy, Developmental Biology

الوصف: Lung-resident (LR) mesenchymal stem and stromal cells (MSCs) are key elements of the alveolar niche and fundamental regulators of homeostasis and regeneration. We interrogated their function during virus-induced lung injury using the highly prevalent respiratory syncytial virus (RSV) which causes severe outcomes in infants. We applied complementary approaches with primary pediatric LR-MSCs and a state-of-the-art model of human RSV infection in lamb. Remarkably, RSV-infection of pediatric LR-MSCs led to a robust activation, characterized by a strong antiviral and pro-inflammatory phenotype combined with mediators related to T cell function. In line with this, following in vivo infection, RSV invades and activates LR-MSCs, resulting in the expansion of the pulmonary MSC pool. Moreover, the global transcriptional response of LR-MSCs appears to follow RSV disease, switching from an early antiviral signature to repair mechanisms including differentiation, tissue remodeling, and angiogenesis. These findings demonstrate the involvement of LR-MSCs during virus-mediated acute lung injury and may have therapeutic implications.
Author summary This work identifies a novel function of lung-resident MSCs during virus-induced acute lung injury. These findings contribute to the understanding of host response and lung repair mechanisms during a highly prevalent clinical situation and may have therapeutic implications.

وصف الملف: application/pdf; journal.ppat.1009789.pdf - application/pdf

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f5c141c2012e2ea49a9660f9a7503c74
http://europepmc.org/articles/PMC8351988

المؤلفون: Schmidinger, Barbara, Petri, Kristina, Lettl, Clara, Li, Hong, Namineni, Sukumar, Ishikawa-Ankerhold, Hellen, Jiménez-Soto, Luisa Fernanda, Haas, Rainer

المصدر: PLoS Pathogens; 2/17/2022, Vol. 18 Issue 2, p1-29, 29p

مصطلحات موضوعية: ANNEXINS, TOLL-like receptors, HELICOBACTER pylori, MOLECULAR recognition, GAMMA-glutamyltransferase, GASTRIC mucosa, LIPOPOLYSACCHARIDES, GASTRIC diseases

مستخلص: Helicobacter pylori colonizes half of the global population and causes gastritis, peptic ulcer disease or gastric cancer. In this study, we were interested in human annexin (ANX), which comprises a protein family with diverse and partly unknown physiological functions, but with a potential role in microbial infections and possible involvement in gastric cancer. We demonstrate here for the first time that H. pylori is able to specifically bind ANXs. Binding studies with purified H. pylori LPS and specific H. pylori LPS mutant strains indicated binding of ANXA5 to lipid A, which was dependent on the lipid A phosphorylation status. Remarkably, ANXA5 binding almost completely inhibited LPS-mediated Toll-like receptor 4- (TLR4) signaling in a TLR4-specific reporter cell line. Furthermore, the interaction is relevant for gastric colonization, as a mouse-adapted H. pylori increased its ANXA5 binding capacity after gastric passage and its ANXA5 incubation in vitro interfered with TLR4 signaling. Moreover, both ANXA2 and ANXA5 levels were upregulated in H. pylori-infected human gastric tissue, and H. pylori can be found in close association with ANXs in the human stomach. Furthermore, an inhibitory effect of ANXA5 binding for CagA translocation could be confirmed. Taken together, our results highlight an adaptive ability of H. pylori to interact with the host cell factor ANX potentially dampening innate immune recognition. Author summary: H. pylori is very well adapted to its natural habitat, the human gastric mucosa. For this purpose, the bacterium has evolved a number of highly specific virulence factors, such as the cag-type IV secretion system, vacuolating cytotoxin A (VacA) or secreted gamma-glutamyl transpeptidase. An important function of these bacterial factors is to manipulate the host immune response to enable a chronic H. pylori infection. The present work identifies a new player in this process. Here, we have discovered that H. pylori, as well as several other bacterial species, can bind human annexins (ANX), suggesting a more widespread phenomenon. We show that H. pylori specifically binds ANXA5 via lipid A. The interaction is strictly dependent on calcium and modulated by the phosphorylation status of lipid A. Notably, ANXA5 binding strongly inhibits LPS-mediated Toll-like receptor 4 (TLR4) signal transduction, suggesting that H. pylori exploits ANXs binding to avoid its recognition by this important receptor of the innate immune system. The study thus provides novel molecular and mechanistic insights into a further strategy of H. pylori to successfully evade recognition by the host. [ABSTRACT FROM AUTHOR]

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المؤلفون: Doorduijn, Dennis J., Heesterbeek, Dani A. C., Ruyken, Maartje, de Haas, Carla J. C., Stapels, Daphne A. C., Aerts, Piet C., Rooijakkers, Suzan H. M., Bardoel, Bart W.

المصدر: PLoS Pathogens; 11/9/2021, Vol. 17 Issue 11, p1-25, 25p

مصطلحات موضوعية: BACTERIAL cells, POLYMERIZATION, GRAM-negative bacteria, PATHOGENIC bacteria, ESCHERICHIA coli O157:H7, LIPOPOLYSACCHARIDES, COMPOSITE membranes (Chemistry)

مستخلص: Complement proteins can form membrane attack complex (MAC) pores that directly kill Gram-negative bacteria. MAC pores assemble by stepwise binding of C5b, C6, C7, C8 and finally C9, which can polymerize into a transmembrane ring of up to 18 C9 monomers. It is still unclear if the assembly of a polymeric-C9 ring is necessary to sufficiently damage the bacterial cell envelope to kill bacteria. In this paper, polymerization of C9 was prevented without affecting binding of C9 to C5b-8, by locking the first transmembrane helix domain of C9. Using this system, we show that polymerization of C9 strongly enhanced damage to both the bacterial outer and inner membrane, resulting in more rapid killing of several Escherichia coli and Klebsiella strains in serum. By comparing binding of wildtype and 'locked' C9 by flow cytometry, we also show that polymerization of C9 is impaired when the amount of available C9 per C5b-8 is limited. This suggests that an excess of C9 is required to efficiently form polymeric-C9. Finally, we show that polymerization of C9 was impaired on complement-resistant E. coli strains that survive killing by MAC pores. This suggests that these bacteria can specifically block polymerization of C9. All tested complement-resistant E. coli expressed LPS O-antigen (O-Ag), compared to only one out of four complement-sensitive E. coli. By restoring O-Ag expression in an O-Ag negative strain, we show that the O-Ag impairs polymerization of C9 and results in complement-resistance. Altogether, these insights are important to understand how MAC pores kill bacteria and how bacterial pathogens can resist MAC-dependent killing. Author summary: In this paper, we focus on how complement proteins, an essential part of the immune system, kill Gram-negative bacteria via so-called membrane attack complex (MAC) pores. The MAC is a large pore that consists of five different proteins. The final component, C9, assembles a ring of up to 18 C9 molecules that damages the bacterial cell envelope. Here, we aimed to better understand if this polymeric-C9 ring is necessary to kill bacteria and if bacteria can interfere in its assembly. We uncover that polymerization of C9 increased the damage to the entire bacterial cell envelope, which resulted in more rapid killing of several Gram-negative species. We also show that some clinical Escherichia coli strains can block polymerization of C9 and survive MAC-dependent killing by modifying sugars in the bacterial cell envelope, namely the O-antigen of lipopolysaccharide. These insights help us to better understand how the immune system kills bacteria and how pathogenic bacteria can survive killing. [ABSTRACT FROM AUTHOR]

: Copyright of PLoS Pathogens is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Brügger, Melanie, Démoulins, Thomas, Barut, G. Tuba, Zumkehr, Beatrice, Oliveira Esteves, Blandina I., Mehinagic, Kemal, Haas, Quentin, Schögler, Aline, Rameix-Welti, Marie-Anne, Eléouët, Jean-François, Moehrlen, Ueli, Marti, Thomas M., Schmid, Ralph A., Summerfield, Artur, Posthaus, Horst, Ruggli, Nicolas, Hall, Sean R. R., Alves, Marco P.

المصدر: PLoS Pathogens; 7/28/2021, Vol. 17 Issue 7, p1-28, 28p

مصطلحات موضوعية: RESPIRATORY syncytial virus infections, MESENCHYMAL stem cells, LUNG infections, T cells, RESPIRATORY syncytial virus, CELL physiology, TISSUE remodeling

مستخلص: Lung-resident (LR) mesenchymal stem and stromal cells (MSCs) are key elements of the alveolar niche and fundamental regulators of homeostasis and regeneration. We interrogated their function during virus-induced lung injury using the highly prevalent respiratory syncytial virus (RSV) which causes severe outcomes in infants. We applied complementary approaches with primary pediatric LR-MSCs and a state-of-the-art model of human RSV infection in lamb. Remarkably, RSV-infection of pediatric LR-MSCs led to a robust activation, characterized by a strong antiviral and pro-inflammatory phenotype combined with mediators related to T cell function. In line with this, following in vivo infection, RSV invades and activates LR-MSCs, resulting in the expansion of the pulmonary MSC pool. Moreover, the global transcriptional response of LR-MSCs appears to follow RSV disease, switching from an early antiviral signature to repair mechanisms including differentiation, tissue remodeling, and angiogenesis. These findings demonstrate the involvement of LR-MSCs during virus-mediated acute lung injury and may have therapeutic implications. Author summary: This work identifies a novel function of lung-resident MSCs during virus-induced acute lung injury. These findings contribute to the understanding of host response and lung repair mechanisms during a highly prevalent clinical situation and may have therapeutic implications. [ABSTRACT FROM AUTHOR]

: Copyright of PLoS Pathogens is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Andreas Pichlmair, Katharina Geiger, Arno Meiler, Georg Kochs, Darya A. Haas, Carola Vogt, Ellen Preuss

المصدر: PLoS Pathogens
PLoS Pathogens, Vol 14, Iss 4, p e1006980 (2018)

مصطلحات موضوعية: 0301 basic medicine, Transcription, Genetic, Cultured tumor cells, Gene Expression, RNA polymerase II, Biochemistry, Polymerases, Gene expression, Transcriptional regulation, Small interfering RNAs, Promoter Regions, Genetic, lcsh:QH301-705.5, Regulation of gene expression, Transcriptional Control, 3. Good health, Cell biology, Nucleic acids, Cell lines, Biological cultures, Transcription factor II B, Research Article, lcsh:Immunologic diseases. Allergy, Immunology, DNA transcription, Biology, Microbiology, Antiviral Agents, 03 medical and health sciences, Viral Proteins, Virology, DNA-binding proteins, Influenza, Human, Genetics, Humans, Gene Regulation, HeLa cells, Non-coding RNA, Molecular Biology, Transcription factor, Biology and Life Sciences, Proteins, Promoter, Cell cultures, Regulatory Proteins, Research and analysis methods, enzymes and coenzymes (carbohydrates), 030104 developmental biology, lcsh:Biology (General), Gene Expression Regulation, biology.protein, Transcription Factor TFIIB, RNA, Parasitology, TATA-binding protein, lcsh:RC581-607, Thogotovirus, Transcription Factors

الوصف: Viruses have evolved a plethora of mechanisms to target host antiviral responses. Here, we propose a yet uncharacterized mechanism of immune regulation by the orthomyxovirus Thogoto virus (THOV) ML protein through engaging general transcription factor TFIIB. ML generates a TFIIB depleted nuclear environment by re-localizing it into the cytoplasm. Although a broad effect on gene expression would be anticipated, ML expression, delivery of an ML-derived functional domain or experimental depletion of TFIIB only leads to altered expression of a limited number of genes. Our data indicate that TFIIB is critically important for the de novo recruitment of Pol II to promoter start sites and that TFIIB may not be required for regulated gene expression from paused promoters. Since many immune genes require de novo recruitment of Pol II, targeting of TFIIB by THOV represents a neat mechanism to affect immune responses while keeping other cellular transcriptional activities intact. Thus, interference with TFIIB activity may be a favourable site for therapeutic intervention to control undesirable inflammation.
Author summary Viruses target the innate immune system at critical vulnerability points. Here we show that the orthomyxovirus Thogoto virus impairs activity of general transcription factor IIB (TFIIB). Surprisingly, impairment of TFIIB function does not result in a general inhibition of transcription but in a rather specific impairment of selective genes. Transcriptome and functional analyses intersected with published CHIP-Seq datasets suggest that affected genes require de novo recruitment of the polymerase complex. Since the innate immune system heavily relies on genes that require de novo recruitment of the polymerase complex, targeting of TFIIB represents a neat mechanism to broadly affect antiviral immunity. Conversely, therapeutic targeting of TFIIB may represent a mechanism to limit pathological side effects caused by overshooting immune reactions.

وصف الملف: application/pdf

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a362430b686285bc6af6613d80f7ab0d
http://europepmc.org/articles/PMC5927403

المؤلفون: Harding, Alfred T., Haas, Griffin D., Chambers, Benjamin S., Heaton, Nicholas S.

المصدر: PLoS Pathogens; 11/15/2019, Vol. 15 Issue 11, p1-22, 22p

مصطلحات موضوعية: INFLUENZA viruses, VIRUS diseases, THERAPEUTICS, VIRAL mutation, ANIMAL rescue, PHARMACOGENOMICS

مستخلص: Influenza A viruses (IAVs) encode their genome across eight, negative sense RNA segments. During viral assembly, the failure to package all eight segments, or packaging a mutated segment, renders the resulting virion incompletely infectious. It is known that the accumulation of these defective particles can limit viral disease by interfering with the spread of fully infectious particles. In order to harness this phenomenon therapeutically, we defined which viral packaging signals were amenable to duplication and developed a viral genetic platform which produced replication competent IAVs that require up to two additional artificial genome segments for full infectivity. The modified and artificial genome segments propagated by this approach are capable of acting as "decoy" segments that, when packaged by coinfecting wild-type viruses, lead to the production of non-infectious viral particles. Although IAVs which require 10 genomic segments for full infectivity are able to replicate themselves and spread in vivo, their genomic modifications render them avirulent in mice. Administration of these viruses, both prophylactically and therapeutically, was able to rescue animals from a lethal influenza virus challenge. Together, our results show that replicating IAVs designed to propagate and spread defective genomic segments represent a potent anti-influenza biological therapy that can target the conserved process of particle assembly to limit viral disease. Author summary: Influenza infections are best prevented via prophylactic vaccination. Vaccination, however, is incompletely efficacious, necessitating the use of anti-influenza therapeutics. To date, several different classes of anti-influenza therapeutics have been developed and used in order to combat these infections. Unfortunately, the incidence of influenza resistance to many of these therapeutics has begun to rise, necessitating the development of new strategies. One such strategy is to mimic the activity of naturally occurring viral particles that harbor defective genomes. These defective interfering particles have the ability to interfere with productive viral assembly, preventing the spread of influenza viruses across the respiratory tract. Furthermore, given the manner in which they target influenza segment packaging, a conserved feature of all influenza A viruses, resistance to this therapeutic strategy is unlikely. Here, we report the development of a genetic platform that allows the production of replicating influenza viruses which require 10 genomic segments to be fully infectious. These viruses are capable of amplifying themselves in isolation, but coinfection with a wild-type virus leads to segment exchange and compromises the spread of both viruses. This interference, while mechanistically distinct from naturally occurring defective particles, was able to target the same viral process and rescue animals exposed to an otherwise lethal viral infection. This viral-based approach may represent a cost effective and scalable method to generate effective anti-influenza therapeutics when vaccines or antiviral drugs become ineffective due to the acquisition of viral resistance mutations. [ABSTRACT FROM AUTHOR]

: Copyright of PLoS Pathogens is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Zhao, Qing, Busch, Benjamin, Jiménez-Soto, Luisa Fernanda, Ishikawa-Ankerhold, Hellen, Massberg, Steffen, Terradot, Laurent, Fischer, Wolfgang, Haas, Rainer

المصدر: PLoS Pathogens; 10/26/2018, Vol. 14 Issue 10, p1-25, 25p

مصطلحات موضوعية: HELICOBACTER pylori, CARCINOEMBRYONIC antigen, TUMOR antigens, CYTOTOXIN synthesis, CELL-mediated cytotoxicity

مستخلص: Translocation of the Helicobacter pylori (Hp) cytotoxin-associated gene A (CagA) effector protein via the cag-Type IV Secretion System (cag-T4SS) into host cells is a hallmark of infection with Hp and a major risk factor for severe gastric diseases, including gastric cancer. To mediate the injection of CagA, Hp uses a membrane-embedded syringe-like molecular apparatus extended by an external pilus-like rod structure that binds host cell surface integrin heterodimers. It is still largely unclear how the interaction of the cag-T4SS finally mediates translocation of the CagA protein into the cell cytoplasm. Recently certain carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), acting as receptor for the Hp outer membrane adhesin HopQ, have been identified to be involved in the process of CagA host cell injection. Here, we applied the CRISPR/Cas9-knockout technology to generate defined human gastric AGS and KatoIII integrin knockout cell lines. Although confocal laser scanning microscopy revealed a co-localization of Hp and β1 integrin heterodimers on gastric epithelial cells, Hp infection studies using the quantitative and highly sensitive Hp β-lactamase reporter system clearly show that neither β1 integrin heterodimers (α1β1, α2β1 or α5β1), nor any other αβ integrin heterodimers on the cell surface are essential for CagA translocation. In contrast, deletion of the HopQ adhesin in Hp, or the simultaneous knockout of the receptors CEACAM1, CEACAM5 and CEACAM6 in KatoIII cells abolished CagA injection nearly completely, although bacterial binding was only reduced to 50%. These data provide genetic evidence that the cag-T4SS-mediated interaction of Hp with cell surface integrins on human gastric epithelial cells is not essential for CagA translocation, but interaction of Hp with CEACAM receptors is facilitating CagA translocation by the cag-T4SS of this important microbe. [ABSTRACT FROM AUTHOR]

: Copyright of PLoS Pathogens is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Hubertus Haas, Jorge Amich, Sven Krappmann, Lukas Schafferer

المصدر: PLoS Pathogens
Amich Elias, J, Schafferer, L, Haas, H & Krappmann, S 2013, ' Regulation of sulphur assimilation is essential for virulence and affects iron homeostasis of the human-pathogenic mould Aspergillus fumigatus ', PL o S Pathogens, vol. 9, no. 8, pp. e1003573 . https://doi.org/10.1371/journal.ppat.1003573
PLoS Pathogens, Vol 9, Iss 8, p e1003573 (2013)

مصطلحات موضوعية: Fungal Physiology, Sulfur metabolism, Human pathogen, Pathogenesis, Aspergillus fumigatus, chemistry.chemical_compound, Mice, lcsh:QH301-705.5, Regulation of gene expression, 0303 health sciences, Fungal protein, Mice, Inbred BALB C, biology, digestive, oral, and skin physiology, 3. Good health, Basic-Leucine Zipper Transcription Factors, Medical Microbiology, Female, Research Article, lcsh:Immunologic diseases. Allergy, inorganic chemicals, Medizinische Fakultät -ohne weitere Spezifikation, Iron, Immunology, Virulence, Mycology, Microbiology, Fungal Proteins, 03 medical and health sciences, Virology, Genetics, Animals, Humans, ddc:610, Molecular Biology, Biology, 030304 developmental biology, Microbial Metabolism, Methionine, 030306 microbiology, Assimilation (biology), biology.organism_classification, respiratory tract diseases, chemistry, lcsh:Biology (General), Parasitology, Pulmonary Aspergillosis, lcsh:RC581-607, Sulfur

الوصف: Sulphur is an essential element that all pathogens have to absorb from their surroundings in order to grow inside their infected host. Despite its importance, the relevance of sulphur assimilation in fungal virulence is largely unexplored. Here we report a role of the bZIP transcription factor MetR in sulphur assimilation and virulence of the human pathogen Aspergillus fumigatus. The MetR regulator is essential for growth on a variety of sulphur sources; remarkably, it is fundamental for assimilation of inorganic S-sources but dispensable for utilization of methionine. Accordingly, it strongly supports expression of genes directly related to inorganic sulphur assimilation but not of genes connected to methionine metabolism. On a broader scale, MetR orchestrates the comprehensive transcriptional adaptation to sulphur-starving conditions as demonstrated by digital gene expression analysis. Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent. The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus. MetR action under sulphur-starving conditions is further required for proper iron regulation, which links regulation of sulphur metabolism to iron homeostasis and demonstrates an unprecedented regulatory crosstalk. Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.
Author Summary Invasive pulmonary aspergillosis (IPA) is a life-threatening disease that affects primarily immunosuppressed patients. During the last decades the incidence of this disease that is accompanied by high mortality rates has increased. Since opportunistic pathogenic fungi, unlike other pathogens, do not express specific virulence factors, it is becoming more and more clear that the elucidation of fungal metabolism is an essential task to understand fungal pathogenicity and to identify novel antifungal targets. In this work we report genetic inactivation of the sulphur transcription regulator MetR in Aspergillus fumigatus and subsequent study of the resulting phenotypes and transcriptional deregulation of the mutant. Here we show that regulation of sulphur assimilation is an essential process for the manifestation of IPA. Moreover, a regulatory connection between sulphur metabolism and iron homeostasis, a further essential virulence determinant of A. fumigatus, is demonstrated in this study for the first time. A deeper knowledge of sulphur metabolism holds the promise of increasing our understanding of fungal virulence and might lead to improved antifungal therapy.

وصف الملف: application/pdf

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f9b9d8c4666e402c7475246858abe66b
http://europepmc.org/articles/PMC3757043

المؤلفون: Doorduijn, Dennis J., Heesterbeek, Dani A. C., Ruyken, Maartje, de Haas, Carla J. C., Stapels, Daphne A. C., Aerts, Piet C., Rooijakkers, Suzan H. M., Bardoel, Bart W.

المصدر: PLoS Pathogens; 8/8/2022, Vol. 18 Issue 8, p1-2, 2p

مصطلحات موضوعية: BACTERIAL cells, POLYMERIZATION, FLOW cytometry

مستخلص: Bacteria were stained with AF488-labelled mouse anti-polymeric-C9 aE11-antibody (c) and Sytox to determine the percentage of cells that has a damaged bacterial IM (d) by flow cytometry. e) Bacterial cell pellets were analyzed by SDS-PAGE for in-gel fluorescence of Cy5-labelled C9wt to distinguish monomeric-C9 from polymeric-C9. Reference 1 Doorduijn DJ, Heesterbeek DAC, Ruyken M, de Haas CJC, Stapels DAC, Aerts PC, et al. (2021) Polymerization of C9 enhances bacterial cell envelope damage and killing by membrane attack complex pores. [Extracted from the article]

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