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Legionella metaeffector MavL reverses ubiquitin ADP-ribosylation via a conserved arginine-specific macrodomain
The pathogen Legionella pneumophila mediates NAD+-dependent ubiquitination pathways upon infection. Here, the authors show the Legionella effector MavL reverses ubiquitin ADP-ribosylation to regulate these pathways. MavL represents a new macrodomain class specific for reversal of arginine ADP-ribosylation with distinct ADP-ribose binding features.
- Zhengrui Zhang
- , Jiaqi Fu
- & Chittaranjan Das
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Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin
Paeniclostridium sordellii hemorrhagic toxin (TcsH) targets TMPRSS2 to enter the host cells. Here, authors showed the cryo-EM structures of the TcsH-TMPRSS2 complex, providing a toxin-receptor interaction model for large clostridial toxins.
- Ruoyu Zhou
- , Liuqing He
- & Liang Tao
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A nanoparticle-based sonodynamic therapy reduces Helicobacter pylori infection in mouse without disrupting gut microbiota
Here, the authors develop a non-antibiotic approach using sonodynamic therapy mediated by a lecithin bilayer-coated poly(lactic-co-glycolic) nanoparticle preloaded with verteporfin, Ver-PLGA@Lecithin, to treat Helicobacter pylori.
- Tao Liu
- , Shuang Chai
- & Lihua Yang
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Structural dynamics of the CROPs domain control stability and toxicity of Paeniclostridium sordellii lethal toxin
Paeniclostridium sordellii lethal toxin (TcsL) is a potent toxin that can cause toxic shock syndrome. TcsL contains a unique CROPs domain with unclear functions. Here, the authors provide evidence of the CROPs domain’s role in stability and toxicity of TcsL.
- Yao Zhou
- , Xiechao Zhan
- & Liang Tao
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A type VII-secreted lipase toxin with reverse domain arrangement
Here Garrett et al. describe a toxin, TslA, secreted by type VII secretion system that has a reverse domain arrangement compared to other previously characterised substrates. The authors show that TslA is a lipase with antibacterial activity.
- Stephen R. Garrett
- , Nicole Mietrach
- & Tracy Palmer
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Article
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Structural and functional insights into the delivery of a bacterial Rhs pore-forming toxin to the membrane
Bacterial Rhs proteins constitute a diverse family of secreted toxins. Here, the authors present a cryo-electron microscopy structure of an Rhs protein from Pseudomonas aeruginosa and provide insights into the mechanisms by which the protein delivers its encapsulated pore-forming toxin fragment to the bacterial membrane.
- Amaia González-Magaña
- , Igor Tascón
- & David Albesa-Jové
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Unconventional structure and mechanisms for membrane interaction and translocation of the NF-κB-targeting toxin AIP56
Structural and functional characterization of an NF-κB-targeting bacterial toxin reveals an unconventional structure and mechanisms of membrane interaction and translocation.
- Johnny Lisboa
- , Cassilda Pereira
- & Nuno M. S. dos Santos
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Greater wax moth control in apiaries can be improved by combining Bacillus thuringiensis and entrapments
The greater wax moth (GWM) is a major bee pest. Here, the authors show how a pest control method that combines a strain of Bacillus thuringiensis and a lure-based entrapment can help to control GWM using lab experiments and field beehives.
- Bo Han
- , Li Zhang
- & Pingli Dai
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Structural basis for the toxicity of Legionella pneumophila effector SidH
Legionella pneumophila secretes hundreds of effectors to facilitate infection. Here, Sharma et al show that the virulence effector SidH adopts a unique α-helical conformation, leading to toxicity via tRNA binding site and resolve the structural basis of SidH regulation through ubiquitination.
- Rahul Sharma
- , Michael Adams
- & Sagar Bhogaraju
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Rhs NADase effectors and their immunity proteins are exchangeable mediators of inter-bacterial competition in Serratia
Rhs proteins delivered by the Type VI secretion system play a key role in competition between rival bacteria. Here, the authors show that Rhs proteins with exchangeable NAD(P)+ glycohydrolase toxin domains and ‘orphan’ immunity proteins are flexible agents of intraspecies competition in Serratia.
- Martin Hagan
- , Genady Pankov
- & Sarah J. Coulthurst
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The RIX domain defines a class of polymorphic T6SS effectors and secreted adaptors
Bacteria use the type VI secretion system (T6SS) to deliver toxic effectors into bacterial or eukaryotic cells. Here, Kanarek et al. identify a protein domain, RIX, that defines a class of polymorphic T6SS effectors with antibacterial and anti-eukaryotic toxic domains, and that enables T6SS-mediated delivery of other effectors.
- Katarzyna Kanarek
- , Chaya Mushka Fridman
- & Dor Salomon
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Acquisition, co-option, and duplication of the rtx toxin system and the emergence of virulence in Kingella
The bacterial genus Kingella includes pathogenic species that secrete a toxin called RtxA, which is absent in commensal species. Here, Morreale et al. identify key steps in the evolutionary transition from commensal to pathogen, including horizontal gene transfer of the toxin-encoding genes, co-option of an existing secretion system, and gene duplication.
- Daniel P. Morreale
- , Eric A. Porsch
- & Paul J. Planet
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Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2
Botulinum neurotoxin E (BoNT/E) is a major cause of botulism and paradoxically also a drug in clinical trial. Here, the authors show that BoNT/E binding and uptake require glycosylation of its host receptor SV2 with high selectivity for SV2A and SV2B over SV2C.
- Zheng Liu
- , Pyung-Gang Lee
- & Rongsheng Jin
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Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii
Rapid antibiotic resistance in bacteria is putting pressure on both existing therapies as well as the development pipeline. Here, the authors present a dual-acting anti-virulence treatment that evades antibiotic resistance mechanisms and remains effective against Top Priority pathogens.
- Christopher Jonkergouw
- , Ngong Kodiah Beyeh
- & Markus B. Linder
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A secreted effector with a dual role as a toxin and as a transcriptional factor
Bacteria can deliver toxic effector proteins into the cytosol of neighboring cells. Here, the authors show that Yersinia pseudotuberculosis secretes an effector that modulates gene expression in neighboring cells of the same species and inhibits the growth of other competitors.
- Dandan Wang
- , Lingfang Zhu
- & Xihui Shen
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Article
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Suicidal chemotaxis in bacteria
Bacteria respond to nutrients and other compounds via chemotaxis, but little is known of their responses to antibiotics. By tracking cells in antibiotic gradients, the authors show that surface-attached Pseudomonas aeruginosa move towards antibiotics in what appears to be a suicidal attack strategy.
- Nuno M. Oliveira
- , James H. R. Wheeler
- & Kevin R. Foster
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Article
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Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms
Here, the authors perform large-scale high-resolution Parkinson’s disease metagenomics analyses, revealing widespread dysbiosis characterized by overabundance of pathogens, immunogens, toxicants, and curli, reduction in neuroprotective and antiinflammatory molecules, and dysregulated neuroactive signaling.
- Zachary D. Wallen
- , Ayse Demirkan
- & Haydeh Payami
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Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia
Enterotoxigenic Escherichia coli infections have been linked to non-diarrheal sequelae however, the reasons for this are unclear. Here, the authors present an additional role of heat-labile toxin in disrupting the structure and function of intestinal epithelial cells.
- Alaullah Sheikh
- , Brunda Tumala
- & James M. Fleckenstein
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Identification of TFPI as a receptor reveals recombination-driven receptor switching in Clostridioides difficile toxin B variants
Toxin B (TcdB) is a major exotoxin responsible for diseases associated with C. difficile infection. Here, Tian et al. show that several TcdB subtypes do not recognize the established FZD receptors, and identify a different host protein (TFPI) as a receptor for subtypes TcdB4 and TcdB10.
- Songhai Tian
- , Xiaozhe Xiong
- & Min Dong
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A toxin-deformation dependent inhibition mechanism in the T7SS toxin-antitoxin system of Gram-positive bacteria
Antimicrobial toxins are secreted by bacteria to kill rival species. Here the authors report the mechanism of inhibition of EsaD, a toxin secreted by some S. aureus strains to kill competitors that lack the antitoxin EsaG, showing marked mechanistic differences to other Type II toxin-antitoxin systems.
- Yongjin Wang
- , Yang Zhou
- & Zhi-Min Zhang
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Cryo-EM structures of the translocational binary toxin complex CDTa-bound CDTb-pore from Clostridioides difficile
Binary toxin translocation system consists of an enzymatic subunit and translocation pore. Here, the authors report the high-resolution cryo-EM structure of Clostridioides difficile binary toxin, comprising ADP-ribosyltransferase CDTa bound to the CDTb pore and revealing translocational unfolding of CDTa in the CDTb-pore.
- Akihiro Kawamoto
- , Tomohito Yamada
- & Hideaki Tsuge
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A single transcription factor facilitates an insect host combating Bacillus thuringiensis infection while maintaining fitness
Plutella xylostella endures Bt toxins with no performance costs. This study reveals how, depending on the presence of the toxin, this insect modifies MAPK phosphorylation to modulate the transcription factor FTZ-F1 binding, to up- or down- regulate Bt receptors or non-receptor (resistant) paralogs.
- Zhaojiang Guo
- , Le Guo
- & Youjun Zhang
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Proteolytic processing induces a conformational switch required for antibacterial toxin delivery
Contact-dependent growth inhibition (CDI) is an important mechanism of bacterial competition. Here, Bartelli et al. show that proteolytic processing of a CDI toxin induces a conformational switch required for translocation into target bacteria.
- Nicholas L. Bartelli
- , Victor J. Passanisi
- & Christopher S. Hayes
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MARTX toxin of Vibrio vulnificus induces RBC phosphatidylserine exposure that can contribute to thrombosis
The pathophysiological mechanism of venous thrombosis associated with Vibrio vulnificus infection remains largely unknown. In this work, the authors investigate this association, focusing on effects of the pore-forming MARTX toxin of V. vulnificus on red blood cells, and the utilisation of a rat venous thrombosis model.
- Han Young Chung
- , Yiying Bian
- & Sang Ho Choi
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De novo determination of mosquitocidal Cry11Aa and Cry11Ba structures from naturally-occurring nanocrystals
An environmentally safe means of mosquito control is the application of Bacillus thuringiensis israelensis, which produces a cocktail of four naturally crystalline proteins exclusively toxic to mosquito. Here the authors report the atomic-resolution structures of Bti Cry11Aa and related Btj Cry11Ba solved de novo through Serial Femtosecond Crystallography on naturally-occurring nanocrystals.
- Guillaume Tetreau
- , Michael R. Sawaya
- & Jacques-Philippe Colletier
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Paeniclostridium sordellii hemorrhagic toxin targets TMPRSS2 to induce colonic epithelial lesions
Paeniclostridium sordellii is an opportunistic pathogen that can occur and be fatal in women undergoing abortion or childbirth. The pathogenesis of a hemorrhagic toxin, TcsH, produced by this bacteria, remains unknown. Here, authors carry out genome-wide screens to identify pathologically relevant host factors of TcsH.
- Xingxing Li
- , Liuqing He
- & Liang Tao
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A proteolytically activated antimicrobial toxin encoded on a mobile plasmid of Bacteroidales induces a protective response
The bacterium Phocaeicola vulgatus is commonly found in the human gut. Here, the authors show that the microorganism produces an antibacterial toxin that targets the LPS core glycan of closely related species and induces a response that partially protects cells from multiple antimicrobial toxins.
- Jordan C. Evans
- , Valentina Laclare McEneany
- & Laurie E. Comstock
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Mechanism of threonine ADP-ribosylation of F-actin by a Tc toxin
Entomopathogenic bacteria used for pest control secrete potent Tc toxins. Here, the authors combine biochemistry, solution and solid-state NMR spectroscopy and cryo-EM to show in atomic detail how the toxin disrupts the host cell cytoskeleton and kills the target cell.
- Alexander Belyy
- , Florian Lindemann
- & Stefan Raunser
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RNase III CLASH in MRSA uncovers sRNA regulatory networks coupling metabolism to toxin expression
Regulatory small RNA (sRNA) interact with mRNAs to regulate their stability, transcription, and translation via diverse mechanisms. Here, McKellar et al. apply RNase IIICLASH of multi-drug resistant Staphylococcus aureus under different culture conditions to link the network of RNA-RNA interactions to environmental conditions and find that the production of small membrane-permeabilizing toxins is strongly regulated by sRNAs.
- Stuart W. McKellar
- , Ivayla Ivanova
- & Sander Granneman
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Mounting, structure and autocleavage of a type VI secretion-associated Rhs polymorphic toxin
Rearrangement hot spots (Rhs) proteins are bacterial polymorphic toxin systems. Here, the authors show that Rhs1 forms a complex with the Type VI secretion system (T6SS) spike protein VgrG and the EagR chaperone. They also present the cryo-EM structure of the Rhs1-EagR complex and propose a model for Rhs loading and delivery by the T6SS.
- Dukas Jurėnas
- , Leonardo Talachia Rosa
- & Eric Cascales
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Toxin secretion and trafficking by Mycobacterium tuberculosis
The tuberculosis necrotizing toxin (TNT) is the major cytotoxicity factor of M. tuberculosis (Mtb). Mtb possesses five type VII secretion systems (ESX). Pajuelo et al. show that the ESX-4 system is required for TNT secretion and that ESX-2 and ESX-4 systems work in concert with ESX-1 to permeabilize the phagosomal membrane and enable trafficking of TNT into the cytoplasm of macrophages infected with Mtb.
- David Pajuelo
- , Uday Tak
- & Michael Niederweis
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The cell envelope of Staphylococcus aureus selectively controls the sorting of virulence factors
The pathogen Staphylococcus aureus releases several pore-forming toxins, termed leukocidins, that kill immune cells. Here, Zheng et al. show that the retention of a leukocidin on bacterial cells and its release are modulated by lipoteichoic acid and a membrane lipid, which also control the sorting of other surface-associated proteins.
- Xuhui Zheng
- , Gerben Marsman
- & Victor J. Torres
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Toxin import through the antibiotic efflux channel TolC
Bacteria can secrete diffusible protein toxins that kill competing bacteria. Here, the authors use biochemical, biophysical and structural analyses to show how one of these toxins exploits TolC (a major antibiotic efflux channel) to transport itself across the outer membrane of target cells.
- Nicholas G. Housden
- , Melissa N. Webby
- & Colin Kleanthous
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The bacterial toxin ExoU requires a host trafficking chaperone for transportation and to induce necrosis
Phospholipase ExoU from Pseudomonas aeruginosa acts on plasma membrane lipids in infected cells, causing membrane rupture and host cell necrosis. Here, Deruelle et al. show that once injected into the host cytoplasm, ExoU requires a host chaperone found on secretory vesicles to reach the plasma membrane and exerts its phospholipase activity.
- Vincent Deruelle
- , Stéphanie Bouillot
- & Philippe Huber
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Control of membrane barrier during bacterial type-III protein secretion
Type-III secretion systems (T3SSs) are capable of translocating proteins with high speed while maintaining the membrane barrier for small molecules. Here, a structure-function analysis of the T3SS pore complex elucidates the precise mechanisms enabling the gating and the conformational changes required for protein substrate secretion.
- Svenja Hüsing
- , Manuel Halte
- & Thibaud T. Renault
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The extracellular contractile injection system is enriched in environmental microbes and associates with numerous toxins
The extracellular Contractile Injection System (eCIS) is a toxin-delivery particle that mediates interactions between bacteria and their invertebrate hosts. Here, the authors catalogue eCIS loci from 1,249 prokaryotic genomes, showing enrichment in non-pathogenic environmental microbes, and identifying eCIS-associated toxins that inhibit the growth of bacteria and/or yeast.
- Alexander Martin Geller
- , Inbal Pollin
- & Asaf Levy
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Article
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Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection
Chondroitin sulfate proteoglycan 4 (CSPG4) is a potential receptor for C. difficile toxin B (TcdB) during C. difficile infections (CDIs). Here, the cryo-EM structure of a TcdB–CSPG4 complex and CDI mouse models offer insights into CSPG4 role in CDIs and suggest a therapeutic strategy targeting TcdB.
- Peng Chen
- , Ji Zeng
- & Rongsheng Jin
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Article
| Open Access
Coagulase-negative staphylococci release a purine analog that inhibits Staphylococcus aureus virulence
Coagulase-negative staphylococci and Staphylococcus aureus colonize similar niches in mammals. Here, Chin et al. show that a coagulase-negative staphylococcus secretes 6-thioguanine, a purine analog that suppresses S. aureus growth and virulence by inhibiting de novo purine biosynthesis and toxin production.
- Denny Chin
- , Mariya I. Goncheva
- & David E. Heinrichs
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Article
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Spatiotemporal persistence of multiple, diverse clades and toxins of Corynebacterium diphtheriae
Cases of diphtheria have increased in recent years. Here, the authors analyse the genomes of 502 Corynebacterium diphtheriae isolates across 16 countries and territories over 122 years, describing an increase in antimicrobial resistance genes and identifying toxin variants.
- Robert C. Will
- , Thandavarayan Ramamurthy
- & Ankur Mutreja
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Article
| Open Access
Droplet printing reveals the importance of micron-scale structure for bacterial ecology
The spatial arrangement of bacterial strains and species within microbial communities is considered crucial for their ecology. Here, Krishna Kumar et al. use a droplet-based printing method to arrange different bacterial genotypes across a sub-millimetre array, and show that micron-scale changes in spatial distributions can drive major shifts in ecology.
- Ravinash Krishna Kumar
- , Thomas A. Meiller-Legrand
- & Kevin R. Foster
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Contact-independent killing mediated by a T6SS effector with intrinsic cell-entry properties
Bacteria can use type VI secretion systems (T6SSs) to inject toxic effector proteins into adjacent cells, in a contact-dependent manner. Here, the authors provide evidence of contact-independent killing by a T6SS effector that is secreted into the extracellular milieu and then taken up by other bacterial cells.
- Li Song
- , Junfeng Pan
- & Xihui Shen
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Article
| Open Access
Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis
Tuberculosis necrotizing toxin (TNT) is secreted by Mycobacterium tuberculosis to kill host cells. Here, Tak, Dokland and Niederweis show that proteins EsxE and EsxF form membrane-spanning hetero-oligomeric pores that are important for TNT secretion.
- Uday Tak
- , Terje Dokland
- & Michael Niederweis
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Article
| Open Access
The evolution of tit-for-tat in bacteria via the type VI secretion system
Game theory has contributed much to the understanding of social evolution. In an elegant combination of experimental tests and modelling, this study suggests that when bacteria face intense competition, repeated retaliation outcompetes a single tit-for-tat response to attack.
- William P. J. Smith
- , Maj Brodmann
- & Kevin R. Foster
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Article
| Open Access
MAPK-dependent hormonal signaling plasticity contributes to overcoming Bacillus thuringiensis toxin action in an insect host
Bacillus thuringiensis (Bt) is an important bioinsecticide, but high-level resistance has been rapidly evolving in agricultural pests. Here, Guo et al. show that the MAPK cascade can be activated by enhanced upstream insect hormone signals to counter Bt virulence in the diamondback moth.
- Zhaojiang Guo
- , Shi Kang
- & Youjun Zhang
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Article
| Open Access
Intramolecular chaperone-mediated secretion of an Rhs effector toxin by a type VI secretion system
Bacterial Rhs proteins with toxic domains are often secreted by type VI secretion systems. Here, the authors show that one of these proteins self-cleaves into three fragments, with the Rhs core and the N-terminal domain facilitating secretion and function of the C-terminal toxic domain.
- Tong-Tong Pei
- , Hao Li
- & Tao G. Dong
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Article
| Open Access
Increased pathogenicity of pneumococcal serotype 1 is driven by rapid autolysis and release of pneumolysin
The mechanisms behind the high invasiveness of Streptococcus pneumoniae serotype 1 are unclear. Here, Jacques et al. show that this feature is due to overproduction and rapid release of pneumolysin, which induces cytotoxicity and breakdown of tight junctions, allowing rapid bacterial dissemination from the respiratory tract into the blood.
- Laura C. Jacques
- , Stavros Panagiotou
- & Aras Kadioglu
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Article
| Open Access
A family of Type VI secretion system effector proteins that form ion-selective pores
Type VI secretion systems (T6SSs) are used by bacteria to inject toxic effector proteins into neighbouring cells. Here, Mariano et al. show that an antibacterial effector from Serratia marcescens forms cation-selective pores that lead to inner-membrane depolarisation and increased outer-membrane permeability.
- Giuseppina Mariano
- , Katharina Trunk
- & Sarah J. Coulthurst
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| Open Access
Typhoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection
Salmonella Typhi produces the typhoid toxin, which damages host cell DNA. Here, Ibler et al. show that the toxin induces a non-canonical DNA damage response mediated by the RPA pathway that drives host cell senescence and facilitates infection.
- Angela E. M. Ibler
- , Mohamed ElGhazaly
- & Daniel Humphreys
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| Open Access
Alternate subunit assembly diversifies the function of a bacterial toxin
Salmonella Typhi produces the typhoid toxin. Here, Fowler et al. show that S. Typhi produces two forms of typhoid toxin that are differentially regulated and display different trafficking properties and different effects when administered to laboratory animals.
- Casey C. Fowler
- , Gabrielle Stack
- & Jorge E. Galán
Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype