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  • Journal article
    Hall A, Gollan B, Helaine S, 2017,

    Toxin-antitoxin systems: reversible toxicity

    , Current Opinion in Microbiology, Vol: 36, Pages: 102-110, ISSN: 1879-0364

    Toxin–antitoxin (TA) systems encoded on the plasmids and chromosomes of bacteria are emerging as key players in stress adaptation. In particular, they have been implicated in the induction of persisters non-growing cells that can evade antibiotic exposure. TA toxins operate by a diverse range of mechanisms, either destructive or conservative, leading to the reversible growth arrest of bacterial cells. Whilst the molecular mechanisms of intoxication are now well understood, we still have very little information on how corrupted cells reawaken. Alongside the phenomenon of conditional cooperativity, new evidence suggests that the effects of some TA toxins can be reversed, allowing non-growing cells to be detoxified and growth to resume.

  • Journal article
    McCarthy RR, Mazon-Moya MJ, Moscoso JA, Hao Y, Lam JS, Bordi C, Mostowy S, Filloux Aet al., 2017,

    Cyclic-di-GMP regulates lipopolysaccharide modification and contributes to Pseudomonas aeruginosa immune evasion

    , Nature Microbiology, Vol: 2, ISSN: 2058-5276

    Pseudomonas aeruginosa is a Gram-negative bacterial pathogen associated with acute and chronic infections. The universal cyclic-di-GMP second messenger is instrumental in the switch from a motile lifestyle to resilient biofilm as in the cystic fibrosis lung. The SadC diguanylate cyclase is associated with this patho-adaptive transition. Here, we identify an unrecognized SadC partner, WarA, which we show is a methyltransferase in complex with a putative kinase, WarB. We established that WarA binds to cyclic-di-GMP, which potentiates its methyltransferase activity. Together, WarA and WarB have structural similarities with the bifunctional Escherichia coli lipopolysaccharide (LPS) O antigen regulator WbdD. Strikingly, WarA influences P. aeruginosa O antigen modal distribution and interacts with the LPS biogenesis machinery. LPS is known to modulate the immune response in the host, and by using a zebrafish infection model, we implicate WarA in the ability of P. aeruginosa to evade detection by the host.

  • Journal article
    Pean CB, Schiebler M, Tan S, Sharrock J, Kierdorf K, Brown K, Maserumule M, Menezes S, Platova M, Bronda K, Guermonprez P, Stramer BM, Floto R, Dionne MS, Pean CB, Schiebler M, Tan SWS, Sharrock JA, Kierdorf K, Brown KP, Maserumule MC, Menezes S, Pilatova M, Bronda K, Guermonprez P, Stramer BM, Floto RA, Dionne MSet al., 2017,

    Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection

    , Nature Communications, Vol: 8, ISSN: 2041-1723

    Mycobacterium tuberculosis remains a global threat to human health yet the molecular mechanisms regulating immunity remain poorly understood. Cytokines can promote or inhibit mycobacterial survivalinside macrophages, andthe underlying mechanisms represent potential targets for host-directed therapies. Here we show that cytokine-STAT signaling promotesmycobacterial survivalwithin macrophages by deregulating lipid droplets via ATG2 repression. In Drosophilainfected withMycobacterium marinum,mycobacterium-induced STAT activitytriggered by unpaired-familycytokinesreduces Atg2 expression, permittingderegulation of lipid droplets. Increased Atg2expression, or reduced macrophage triglyceride biosynthesis,normalizes lipid deposition in infected phagocytes and reduces numbersof viable intracellular mycobacteria. In human macrophages,addition ofIL-6promotes mycobacterial survival and BCG-induced lipid accumulation by a similar, but probably not identical, mechanism. Our results reveal Atg2regulation as amechanism by which cytokines can control lipid droplet homeostasis and consequently resistance to mycobacterial infectionin Drosophila.

  • Journal article
    Dominguez-Huettinger E, Boon NJ, Clarke TB, Tanaka RJet al., 2017,

    Mathematical Modeling of Streptococcus pneumoniae Colonization, Invasive Infection and Treatment

    , FRONTIERS IN PHYSIOLOGY, Vol: 8, ISSN: 1664-042X

    Streptococcus pneumoniae (Sp) is a commensal bacterium that normally resides on the upper airway epithelium without causing infection. However, factors such as co-infection with influenza virus can impair the complex Sp-host interactions and the subsequent development of many life-threatening infectious and inflammatory diseases, including pneumonia, meningitis or even sepsis. With the increased threat of Sp infection due to the emergence of new antibiotic resistant Sp strains, there is an urgent need for better treatment strategies that effectively prevent progression of disease triggered by Sp infection, minimizing the use of antibiotics. The complexity of the host-pathogen interactions has left the full understanding of underlying mechanisms of Sp-triggered pathogenesis as a challenge, despite its critical importance in the identification of effective treatments. To achieve a systems-level and quantitative understanding of the complex and dynamically-changing host-Sp interactions, here we developed a mechanistic mathematical model describing dynamic interplays between Sp, immune cells, and epithelial tissues, where the host-pathogen interactions initiate. The model serves as a mathematical framework that coherently explains various in vitro and in vitro studies, to which the model parameters were fitted. Our model simulations reproduced the robust homeostatic Sp-host interaction, as well as three qualitatively different pathogenic behaviors: immunological scarring, invasive infection and their combination. Parameter sensitivity and bifurcation analyses of the model identified the processes that are responsible for qualitative transitions from healthy to such pathological behaviors. Our model also predicted that the onset of invasive infection occurs within less than 2 days from transient Sp challenges. This prediction provides arguments in favor of the use of vaccinations, since adaptive immune responses cannot be developed de novo in such a short time. We furthe

  • Journal article
    Wang S, Lin Y, Todorova N, Xu Y, Mazo M, Rana S, Leonardo V, Amdursky N, Spicer CD, Alexander BD, Edwards AA, Matthews SJ, Yarovsky I, Stevens MMet al., 2017,

    Facet-dependent interactions of islet amyloid polypeptide with gold nanoparti-cles: implications for fibril formation and peptide-induced lipid membrane dis-ruption

    , Chemistry of Materials, Vol: 29, ISSN: 1520-5002

    A comprehensive understanding of the mechanisms of interaction between proteins or peptides and nanomaterials is crucial for the development of nanomaterial-based diagnos-tics and therapeutics. In this work, we systematically explored the interactions between citrate-capped gold nanoparticles (AuNPs) and islet amyloid polypeptide (IAPP), a 37-amino acid peptide hormone co-secreted with insulin from the pancreatic islet. We uti-lized diffusion-ordered spectroscopy, isothermal titration calorimetry, localized surface plasmon resonance spectroscopy, gel electrophoresis, atomic force microscopy, transmis-sion electron microscopy (TEM), and molecular dynamics (MD) simulations to systemati-cally elucidate the underlying mechanism of the IAPP−AuNP interactions. Because of the presence of a metal-binding sequence motif in the hydrophilic peptide domain, IAPP strongly interacts with the Au surface in both the monomeric and fibrillar states. Circular dichroism showed that AuNPs triggered the IAPP conformational transition from random coil to ordered structures (α-helix and β-sheet), and TEM imaging suggested the accelera-tion of IAPP fibrillation in the presence of AuNPs. MD simulations revealed that the IAPP−AuNP interactions were initiated by the N-terminal domain (IAPP residues 1−19), which subsequently induced a facet-dependent conformational change in IAPP. On a Au(111) surface, IAPP was unfolded and adsorbed directly onto the Au surface, while for the Au(100) surface, it interacted predominantly with the citrate adlayer and retained some helical conformation. The observed affinity of AuNPs for IAPP was further applied to reduce the level of peptide-induced lipid membrane disruption.

  • Journal article
    Larrouy-Maumus G, Layre E, Clark S, Prandi J, Rayner E, Lepore M, de Libero G, Williams A, Puzo G, Gilleron Met al., 2017,

    Protective efficacy of a lipid antigen vaccine in a guinea pig model of tuberculosis

    , VACCINE, Vol: 35, Pages: 1395-1402, ISSN: 0264-410X
  • Conference paper
    Rouse SL, Hawthorne W, Berry J, Matthews Set al., 2017,

    Structural and Mechanistic Insights into Transport of Functional Amyloid Subunits across the Pseudomonas Outer Membrane

    , 61st Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 188A-188A, ISSN: 0006-3495
  • Journal article
    Eldridge MJG, Sanchez Garrido J, Hoben GF, Goddard PJ, Shenoy ARet al., 2017,

    The atypical ubiquitin E2 conjugase UBE2L3 is an indirect caspase-1 target and controls IL-1beta secretion by inflammasomes

    , Cell Reports, Vol: 18, Pages: 1285-1297, ISSN: 2211-1247

    Caspase-1 activation by inflammasome signalling scaffoldsinitiates inflammation and antimicrobial responses. Caspase-1 proteolytically converts newly induced pro-IL-1α into its mature form and directs its secretion, triggers pyroptosis and the release of non-substrate alarmins such as IL-1α and HMGB1. While somecaspase-1 substrates involved in these events are known, the identities and roles of non-proteolytic targets remain unknown. Here we report using unbiased proteomics that the UBE2L3 ubiquitin conjugase is an indirect target of caspase-1. Caspase-1, but not caspase-4, controlled pyroptosis-and ubiquitin-independent proteasomal degradation of UBE2L3 upon canonical and non-canonical inflammasome activation by sterile danger signals and bacterial infection. Mechanistically, UBE2L3 acted post-translationally to promote K48-ubiquitylation and turnover of pro-IL-1β and dampen mature-IL-1β production. UBE2L3 depletion increased pro-IL-1β levels and mature-IL-1βsecretion by inflammasomes. These findings on UBE2L3 as a molecular rheostat have implications for IL-1-driven pathology in hereditary fever syndromes, and autoinflammatory conditions associated with UBE2L3 polymorphisms.

  • Journal article
    Bosi E, Fondi M, Orlandini V, Perrin E, Maida I, de Pascale D, Tutino ML, Parrilli E, Lo Giudice A, Filloux A, Fani Ret al., 2017,

    The pangenome of (Antarctic) Pseudoalteromonas bacteria: evolutionary and functional insights

    , BMC Genomics, Vol: 18, ISSN: 1471-2164

    Background:Pseudoalteromonas is a genus of ubiquitous marine bacteria used as model organisms to study the biological mechanisms involved in the adaptation to cold conditions. A remarkable feature shared by these bacteria is their ability to produce secondary metabolites with a strong antimicrobial and antitumor activity. Despite their biotechnological relevance, representatives of this genus are still lacking (with few exceptions) an extensive genomic characterization, including features involved in the evolution of secondary metabolites production. Indeed, biotechnological applications would greatly benefit from such analysis.Results:Here, we analyzed the genomes of 38 strains belonging to different Pseudoalteromonas species and isolated from diverse ecological niches, including extreme ones (i.e. Antarctica). These sequences were used to reconstruct the largest Pseudoalteromonas pangenome computed so far, including also the two main groups of Pseudoalteromonas strains (pigmented and not pigmented strains). The downstream analyses were conducted to describe the genomic diversity, both at genus and group levels. This allowed highlighting a remarkable genomic heterogeneity, even for closely related strains. We drafted all the main evolutionary steps that led to the current structure and gene content of Pseudoalteromonas representatives. These, most likely, included an extensive genome reduction and a strong contribution of Horizontal Gene Transfer (HGT), which affected biotechnologically relevant gene sets and occurred in a strain-specific fashion. Furthermore, this study also identified the genomic determinants related to some of the most interesting features of the Pseudoalteromonas representatives, such as the production of secondary metabolites, the adaptation to cold temperatures and the resistance to abiotic compounds.Conclusions:This study poses the bases for a comprehensive understanding of the evolutionary trajectories followed in time by this peculiar bact

  • Journal article
    Pearson JS, Giogha C, Muhlen S, Nachbur U, Pham CLL, Zhang Y, Hildebrand JM, Oates CV, Lung TWF, Ingle D, Dagley LF, Bankovacki A, Petrie EJ, Schroeder GN, Crepin VF, Frankel G, Masters SL, Vince J, Murphy JM, Sunde M, Webb AI, Silke J, Hartland ELet al., 2017,

    EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation

    , NATURE MICROBIOLOGY, Vol: 2, ISSN: 2058-5276

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