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  • Journal article
    Krokowski S, Lobato-Márquez D, Mostowy S, 2018,

    Mitochondria promote septin assembly into cages that entrap Shigella for autophagy

    , Autophagy, Vol: 14, Pages: 913-914, ISSN: 1554-8635

    Septins are cytoskeletal proteins implicated in cytokinesis and host-pathogen interactions. During macroautophagy/autophagy of Shigella flexneri, septins assemble into cage-like structures to entrap actin-polymerizing bacteria and restrict their dissemination. How septins assemble to entrap bacteria is not fully known. We discovered that mitochondria support septin cage assembly to promote autophagy of Shigella. Consistent with roles for the cytoskeleton in mitochondrial dynamics, we showed that DNM1L/DRP1 (dynamin 1 like) can interact with septins to enhance mitochondrial fission. Remarkably, Shigella fragment mitochondria and escape from septin cage entrapment in order to avoid autophagy. These results uncover a close relationship between mitochondria and septin assembly, and identify a new role for mitochondria in bacterial autophagy.

  • Conference paper
    Way MC, Pfanzelter J, Mostowy S, 2016,

    Septins suppress the release of Vaccinia virus from infected cells

    , Publisher: Rockefeller University Press, ISSN: 0021-9525
  • Journal article
    Bernal P, Llamas MA, Filloux A, 2018,

    Type VI secretion systems in plant-associated bacteria

    , Environmental Microbiology, Vol: 20, Pages: 1-15, ISSN: 1462-2912

    The type VI secretion system (T6SS) is a bacterial nanomachine used to inject effectors into prokaryotic or eukaryotic cells and is thus involved in both host manipulation and interbacterial competition. The T6SS is widespread among Gram‐negative bacteria, mostly within the Proteobacterium Phylum. This secretion system is commonly found in commensal and pathogenic plant‐associated bacteria. Phylogenetic analysis of phytobacterial T6SS clusters shows that they are distributed in the five main clades previously described (group 1–5). The even distribution of the system among commensal and pathogenic phytobacteria suggests that the T6SS provides fitness and colonization advantages in planta and that the role of the T6SS is not restricted to virulence. This manuscript reviews the phylogeny and biological roles of the T6SS in plant‐associated bacteria, highlighting a remarkable diversity both in terms of mechanism and function.

  • Journal article
    Mullineaux-Sanders C, Colins JW, Ruano-Gallego D, Levy M, Pevsner-Fischer M, Glegola-Madejska IT, Sagfors AM, Wong JLC, Elinav E, Crepin VF, Frankel GMet al., 2017,

    Citrobacter rodentium relies on commensals for colonization of the colonic mucosa

    , Cell Reports, Vol: 21, Pages: 3381-3389, ISSN: 2211-1247

    We investigated the role of commensals at the peak of infection with the colonic mouse pathogen Citrobacter rodentium. Bioluminescent and kanamycin (Kan)-resistant C. rodentium persisted avirulently in the cecal lumen of mice continuously treated with Kan. A single Kan treatment was sufficient to displace C. rodentium from the colonic mucosa, a phenomenon not observed following treatment with vancomycin (Van) or metronidazole (Met). Kan, Van, and Met induce distinct dysbiosis, suggesting C. rodentium relies on specific commensals for colonic colonization. Expression of the master virulence regulator ler is induced in germ-free mice, yet C. rodentium is only seen in the cecal lumen. Moreover, in conventional mice, a single Kan treatment was sufficient to displace C. rodentium constitutively expressing Ler from the colonic mucosa. These results show that expression of virulence genes is not sufficient for colonization of the colonic mucosa and that commensals are essential for a physiological infection course.

  • Journal article
    Johnson R, Ravenhall M, Pickard D, Dougan G, Byrne A, Frankel GMet al., 2017,

    Comparison of Salmonella enterica serovars Typhi and Typhimurium reveals typhoidal-specific responses to bile

    , Infection and Immunity, Vol: 86, ISSN: 0019-9567

    Salmonella enterica serovars Typhi and Typhimurium cause typhoid fever and gastroenteritis respectively. A unique feature of typhoid infection is asymptomatic carriage within the gallbladder, which is linked with S. Typhi transmission. Despite this, S. Typhi responses to bile have been poorly studied. RNA-Seq of S. Typhi Ty2 and a clinical S. Typhi isolate belonging to the globally dominant H58 lineage (129-0238), as well as S. Typhimurium 14028, revealed that 249, 389 and 453 genes respectively were differentially expressed in the presence of 3% bile compared to control cultures lacking bile. fad genes, the actP-acs operon, and putative sialic acid uptake and metabolism genes (t1787-t1790) were upregulated in all strains following bile exposure, which may represent adaptation to the small intestine environment. Genes within the Salmonella pathogenicity island 1 (SPI-1), encoding a type IIII secretion system (T3SS), and motility genes were significantly upregulated in both S. Typhi strains in bile, but downregulated in S. Typhimurium. Western blots of the SPI-1 proteins SipC, SipD, SopB and SopE validated the gene expression data. Consistent with this, bile significantly increased S. Typhi HeLa cell invasion whilst S. Typhimurium invasion was significantly repressed. Protein stability assays demonstrated that in S. Typhi the half-life of HilD, the dominant regulator of SPI-1, is three times longer in the presence of bile; this increase in stability was independent of the acetyltransferase Pat. Overall, we found that S. Typhi exhibits a specific response to bile, especially with regards to virulence gene expression, which could impact pathogenesis and transmission.

  • Journal article
    Portaliou AG, Tsolis KC, Loos MS, Balabanidou V, Rayo J, Tsirigotaki A, Crepin VF, Frankel G, Kalodimos CG, Karamanou S, Economou Aet al., 2017,

    Hierarchical protein targeting and secretion is controlled by an affinity switch in the type III secretion system of enteropathogenic Escherichia coli

    , EMBO JOURNAL, Vol: 36, Pages: 3517-3531, ISSN: 0261-4189
  • Journal article
    Torraca V, Mostowy S, 2017,

    Zebrafish Infection: from Pathogenesis to Cell Biology

    , Trends in Cell Biology, Vol: 28, Pages: 143-156, ISSN: 0962-8924

    The study of host–pathogen interactions has illuminated fundamental research avenues in both infection and cell biology. Zebrafish (Danio rerio) larvae are genetically tractable, optically accessible, and present a fully functional innate immune system with macrophages and neutrophils that mimic their mammalian counterparts. A wide variety of pathogenic bacteria have been investigated using zebrafish models, providing unprecedented resolution of the cellular response to infection in vivo. In this review, we illustrate how zebrafish models have contributed to our understanding of cellular microbiology by providing an in vivo platform to study host–pathogen interactions from the single cell to whole animal level. We also highlight discoveries made from zebrafish infection that hold great promise for translation into novel therapies for humans.

  • Journal article
    Lee PP, Lobato-Marquez D, Pramanik N, Sirianni A, Daza-Cajigal V, Rivers E, Cavazza A, Bouma G, Moulding D, Hultenby K, Westerberg LS, Hollinshead M, Lau Y-L, Burns SO, Mostowy S, Bajaj-Elliott M, Thrasher AJet al., 2017,

    Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells

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

    Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott–Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage-like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention.

  • Journal article
    Helle SCJ, Feng Q, Aebersold MJ, Hirt L, Gruter RR, Vahid A, Sirianni A, Mostowy S, Snedeker JG, Saric A, Idema T, Zambelli T, Kornmann Bet al., 2017,

    Mechanical force induces mitochondrial fission

    , ELIFE, Vol: 6, ISSN: 2050-084X
  • Journal article
    Cepeda-Molero M, Berger CN, Walsham ADS, Ellis SJ, Wemyss-Holden S, Schueller S, Frankel G, Angel Fernandez Let al., 2017,

    Attaching and effacing (A/E) lesion formation by enteropathogenic E. coli on human intestinal mucosa is dependent on non-LEE effectors

    , PLoS Pathogens, Vol: 13, ISSN: 1553-7366

    Enteropathogenic E. coli (EPEC) is a human pathogen that causes acute and chronic pediatric diarrhea. The hallmark of EPEC infection is the formation of attaching and effacing (A/E) lesions in the intestinal epithelium. Formation of A/E lesions is mediated by genes located on the pathogenicity island locus of enterocyte effacement (LEE), which encode the adhesin intimin, a type III secretion system (T3SS) and six effectors, including the essential translocated intimin receptor (Tir). Seventeen additional effectors are encoded by genes located outside the LEE, in insertion elements and prophages. Here, using a stepwise approach, we generated an EPEC mutant lacking the entire effector genes (EPEC0) and intermediate mutants. We show that EPEC0 contains a functional T3SS. An EPEC mutant expressing intimin but lacking all the LEE effectors but Tir (EPEC1) was able to trigger robust actin polymerization in HeLa cells and mucin-producing intestinal LS174T cells. However, EPEC1 was unable to form A/E lesions on human intestinal in vitro organ cultures (IVOC). Screening the intermediate mutants for genes involved in A/E lesion formation on IVOC revealed that strains lacking non-LEE effector/s have a marginal ability to form A/E lesions. Furthermore, we found that Efa1/LifA proteins are important for A/E lesion formation efficiency in EPEC strains lacking multiple effectors. Taken together, these results demonstrate the intricate relationships between T3SS effectors and the essential role non-LEE effectors play in A/E lesion formation on mucosal surfaces.

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

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