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Journal articleChorev DS, Baker LA, Wu D, et al., 2018,
Protein assemblies ejected directly from native membranes yield complexes for mass spectrometry
, SCIENCE, Vol: 362, Pages: 829-+, ISSN: 0036-8075 -
Journal articleDortet L, Potron A, Bonnin RA, et al., 2018,
Rapid detection of colistin resistance in Acinetobacter baumannii using MALDI-TOF-based lipidomics on intact bacteria
, Scientific Reports, Vol: 8, ISSN: 2045-2322With the dissemination of extremely drug resistant bacteria, colistin is now considered as the last-resort therapy for the treatment of infection caused by Gram-negative bacilli (including carbapenemase producers). Unfortunately, the increase use of colistin has resulted in the emergence of resistance as well. In A. baumannii, colistin resistance is mostly caused by the addition of phosphoethanolamine to the lipid A through the action of a phosphoethanolamine transferase chromosomally-encoded by the pmrC gene, which is regulated by the two-component system PmrA/PmrB. In A. baumannii clinical isolate the main resistance mechanism to colistin involves mutations in pmrA, pmrB or pmrC genes leading to the overexpression of pmrC. Although, rapid detection of resistance is one of the key issues to improve the treatment of infected patient, detection of colistin resistance in A. baumannii still relies on MIC determination through microdilution, which is time-consuming (16–24 h). Here, we evaluated the performance of a recently described MALDI-TOF-based assay, the MALDIxin test, which allows the rapid detection of colistin resistance-related modifications to lipid A (i.e phosphoethanolamine addition). This test accurately detected all colistin-resistant A. baumannii isolates in less than 15 minutes, directly on intact bacteria with a very limited sample preparation prior MALDI-TOF analysis.
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Journal articleDecout A, Silva-Gomes S, Drocourt D, et al., 2018,
Deciphering the molecular basis of mycobacteria and lipoglycan recognition by the C-type lectin Dectin-2
, Scientific Reports, Vol: 8, ISSN: 2045-2322Dectin-2 is a C-type lectin involved in the recognition of several pathogens such as Aspergillus fumigatus, Candida albicans, Schistosoma mansonii, and Mycobacterium tuberculosis that triggers Th17 immune responses. Identifying pathogen ligands and understanding the molecular basis of their recognition is one of the current challenges. Purified M. tuberculosis mannose-capped lipoarabinomannan (ManLAM) was shown to induce signaling via Dectin-2, an activity that requires the (α1 → 2)-linked mannosides forming the caps. Here, using isogenic M. tuberculosis mutant strains, we demonstrate that ManLAM is a bona fide and actually the sole ligand mediating bacilli recognition by Dectin-2, although M. tuberculosis produces a variety of cell envelope mannoconjugates, such as phosphatidyl-myo-inositol hexamannosides, lipomannan or manno(lipo)proteins, that bear (α1 → 2)-linked mannosides. In addition, we found that Dectin-2 can recognize lipoglycans from other bacterial species, such as Saccharotrix aerocolonigenes or the human opportunistic pathogen Tsukamurella paurometabola, suggesting that lipoglycans are prototypical Dectin-2 ligands. Finally, from a structure/function relationship perspective, we show, using lipoglycan variants and synthetic mannodendrimers, that dimannoside caps and multivalent interaction are required for ligand binding to and signaling via Dectin-2. Better understanding of the molecular basis of ligand recognition by Dectin-2 will pave the way for the rational design of potent adjuvants targeting this receptor.
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Journal articleStapels DAC, Hill PWS, Westermann AJ, et al., 2018,
Salmonella persisters undermine host immune defenses during antibiotic treatment
, Science, Vol: 362, Pages: 1156-1160, ISSN: 0036-8075Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of Salmonella species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that Salmonella persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the Salmonella pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing Salmonella cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved.
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Journal articlePfanzelter J, Mostowy S, Way M, 2018,
Septins suppress the release of vaccinia virus from infected cells.
, J Cell Biol, Vol: 217, Pages: 2911-2929Septins are conserved components of the cytoskeleton that play important roles in many fundamental cellular processes including division, migration, and membrane trafficking. Septins can also inhibit bacterial infection by forming cage-like structures around pathogens such as Shigella We found that septins are recruited to vaccinia virus immediately after its fusion with the plasma membrane during viral egress. RNA interference-mediated depletion of septins increases virus release and cell-to-cell spread, as well as actin tail formation. Live cell imaging reveals that septins are displaced from the virus when it induces actin polymerization. Septin loss, however, depends on the recruitment of the SH2/SH3 adaptor Nck, but not the activity of the Arp2/3 complex. Moreover, it is the recruitment of dynamin by the third Nck SH3 domain that displaces septins from the virus in a formin-dependent fashion. Our study demonstrates that septins suppress vaccinia release by "entrapping" the virus at the plasma membrane. This antiviral effect is overcome by dynamin together with formin-mediated actin polymerization.
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Journal articleBernal P, Llamas MA, Filloux A, 2018,
Type VI secretion systems in plant-associated bacteria
, Environmental Microbiology, Vol: 20, Pages: 1-15, ISSN: 1462-2912The 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.
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Journal articleMullineaux-Sanders C, Colins JW, Ruano-Gallego D, et al., 2017,
Citrobacter rodentium relies on commensals for colonization of the colonic mucosa
, Cell Reports, Vol: 21, Pages: 3381-3389, ISSN: 2211-1247We 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.
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Journal articleJohnson R, Ravenhall M, Pickard D, et al., 2017,
Comparison of Salmonella enterica serovars Typhi and Typhimurium reveals typhoidal-specific responses to bile
, Infection and Immunity, Vol: 86, ISSN: 0019-9567Salmonella 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.
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Journal articlePortaliou AG, Tsolis KC, Loos MS, et 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- Author Web Link
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- Citations: 38
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Journal articleCepeda-Molero M, Berger CN, Walsham ADS, et 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: 1553-7366Enteropathogenic 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.
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