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Journal articleO'Neill AM, Thurston TL, Holden DW, 2016,
Erratum for O'Neill et al., Cytosolic Replication of Group A Streptococcus in Human Macrophages.
, mBio, Vol: 7, ISSN: 2161-2129 -
Journal articleFilloux A, Freemont P, 2016,
Structural biology: baseplates in contractile machines
, Nature Microbiology, Vol: 1, ISSN: 2058-5276 -
Journal articleTaglialegna A, Navarro S, Ventura S, et al., 2016,
Staphylococcal Bap Proteins Build Amyloid Scaffold Biofilm Matrices in Response to Environmental Signals
, PLOS Pathogens, Vol: 12, ISSN: 1553-7366Biofilms are communities of bacteria that grow encased in an extracellular matrix that often contains proteins. The spatial organization and the molecular interactions between matrix scaffold proteins remain in most cases largely unknown. Here, we report that Bap protein of Staphylococcus aureus self-assembles into functional amyloid aggregates to build the biofilm matrix in response to environmental conditions. Specifically, Bap is processed and fragments containing at least the N-terminus of the protein become aggregation-prone and self-assemble into amyloid-like structures under acidic pHs and low concentrations of calcium. The molten globule-like state of Bap fragments is stabilized upon binding of the cation, hindering its self-assembly into amyloid fibers. These findings define a dual function for Bap, first as a sensor and then as a scaffold protein to promote biofilm development under specific environmental conditions. Since the pH-driven multicellular behavior mediated by Bap occurs in coagulase-negative staphylococci and many other bacteria exploit Bap-like proteins to build a biofilm matrix, the mechanism of amyloid-like aggregation described here may be widespread among pathogenic bacteria.
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Journal articlePlanamente S, Salih O, Manoli E, et al., 2016,
TssA forms a gp6-like ring attached to the type VI secretion sheath
, EMBO Journal, Vol: 35, Pages: 1613-1627, ISSN: 0261-4189The type VI secretion system (T6SS) is a supra-molecular bacterial complex that resembles phage tails. It is a killing machine which fires toxins into target cells upon contraction of its TssBC sheath. Here, we show that TssA1 is a T6SS component forming dodecameric ring structures whose dimensions match those of the TssBC sheath and which can accommodate the inner Hcp tube. The TssA1 ring complex binds the T6SS sheath and impacts its behaviour in vivo. In the phage, the first disc of the gp18 sheath sits on a baseplate wherein gp6 is a dodecameric ring. We found remarkable sequence and structural similarities between TssA1 and gp6 C-termini, and propose that TssA1 could be a baseplate component of the T6SS. Furthermore, we identified similarities between TssK1 and gp8, the former interacting with TssA1 while the latter is found in the outer radius of the gp6 ring. These observations, combined with similarities between TssF and gp6N-terminus or TssG and gp53, lead us to propose a comparative model between the phage baseplate and the T6SS.
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Journal articleHolmes AH, Gill SK, Hui K, et al., 2016,
Increased airway glucose increases airway bacterial load in hyperglycaemia
, Scientific Reports, Vol: 6, ISSN: 2045-2322Diabetes is associated with increased frequency of hospitalization due to bacterial lung infection.We hypothesize that increased airway glucose caused by hyperglycaemia leads to increasedbacterial loads. In critical care patients, we observed that respiratory tract bacterial colonisationis significantly more likely when blood glucose is high. We engineered mutants in genesaffecting glucose uptake and metabolism (oprB, gltK, gtrS and glk) in Pseudomonas aeruginosa,strain PAO1. These mutants displayed attenuated growth in minimal medium supplemented withglucose as the sole carbon source. The effect of glucose on growth in vivo was tested usingstreptozocin-induced, hyperglycaemic mice, which have significantly greater airway glucose.Bacterial burden in hyperglycaemic animals was greater than control animals when infected withwild type but not mutant PAO1. Metformin pre-treatment of hyperglycaemic animals reducedboth airway glucose and bacterial load. These data support airway glucose as a criticaldeterminant of increased bacterial load during diabetes.
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Journal articleRolhion N, Furniss R, Grabe G, et al., 2016,
Inhibition of nuclear transport of NF-kB p65 by the Salmonella type III secretion system effector SpvD
, Plos Pathogens, Vol: 12, Pages: 1-26, ISSN: 1553-7374Salmonella enterica replicates in macrophages through the action of effector proteins translocated across the vacuolar membrane by a type III secretion system (T3SS). Here we show that the SPI-2 T3SS effector SpvD suppresses proinflammatory immune responses. SpvD prevented activation of an NF-ĸB-dependent promoter and caused nuclear accumulation of importin-α, which is required for nuclear import of p65. SpvD interacted specifically with the exportin Xpo2, which mediates nuclear-cytoplasmic recycling of importins. We propose that interaction between SpvD and Xpo2 disrupts the normal recycling of importin-α from the nucleus, leading to a defect in nuclear translocation of p65 and inhibition of activation of NF-ĸB regulated promoters. SpvD down-regulated pro-inflammatory responses and contributed to systemic growth of bacteria in mice. This work shows that a bacterial pathogen can manipulate host cell immune responses by interfering with the nuclear transport machinery.
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Journal articleHergott CB, Roche AM, Tamashiro E, et al., 2016,
Detection of peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis
, Blood, Vol: 127, Pages: 2460-2471, ISSN: 1528-0020Maintenance of myeloid cell homeostasis requires continuous turnover of phagocytes from the bloodstream, yet whether environmental signals influence phagocyte longevity in the absence of inflammation remains unknown. Here, we show that the gut microbiota regulates the steady-state cellular lifespan of neutrophils and inflammatory monocytes, the two most abundant circulating myeloid cells and key contributors to inflammatory responses. Treatment of mice with broad-spectrum antibiotics, or with the gut-restricted aminoglycoside neomycin alone, accelerated phagocyte turnover and increased the rates of their spontaneous apoptosis. Metagenomic analyses revealed that neomycin altered the abundance of intestinal bacteria bearing γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP), a ligand for the intracellular peptidoglycan sensor Nod1. Accordingly, signaling through Nod1 was both necessary and sufficient to mediate the stimulatory influence of the flora on myeloid cell longevity. Stimulation of Nod1 signaling increased the frequency of lymphocytes in the murine intestine producing the pro-inflammatory cytokine interleukin 17A (IL-17A), and liberation of IL-17A was required for transmission of Nod1-dependent signals to circulating phagocytes. Together, these results define a mechanism through which intestinal microbes govern a central component of myeloid homeostasis and suggest perturbations of commensal communities can influence steady-state regulation of cell fate.
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Journal articlePercy M, Karinou E, Webb A, et al., 2016,
Identification of a lipoteichoic acid glycosyltransferase enzyme reveals that GW-domain containing proteins can be retained in the cell wall of Listeria monocytogenes in the absence of lipoteichoic acid or its modifications
, Journal of Bacteriology, Vol: 198, Pages: 2029-2042, ISSN: 1098-5530Listeria monocytogenes is a food-borne Gram-positive bacterial pathogen and many of its virulence factors are either secreted proteins, or proteins covalently or non-covalently-attached to the cell wall. Previous work has indicated that non-covalently-attached proteins with GW domains are retained in the cell wall by binding to the cell wall polymer lipoteichoic acid (LTA). LTA is a glycerolphosphate polymer, which is modified in L. monocytogenes with galactose and D-alanine residues. We identified Lmo0933 as the cytoplasmic glycosyltransferase required for the LTA glycosylation process and renamed the protein GtlA for glycosyltransferase LTA A. Using L. monocytogenes mutants lacking galactose or D-alanine modifications or the complete LTA polymer, we show that GW-domain proteins are still retained within the cell wall, indicating that other cell wall polymers are involved in the retention of GW-domain proteins. Further experiments reveal peptidoglycan as the binding receptor as a purified GW domainfusion protein can bind to L. monocytogenes cells lacking wall teichoic acid (WTA) as well as purified peptidoglycan derived from a wild-type or WTA-negative strain. With this, we not only identified the first enzyme involved in the LTA glycosylation process, but we also provide new insight into the binding mechanism of non-covalently attached cell wall proteins.
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Journal articleSantos AJM, Durkin C, Helaine S, et al., 2016,
Clustered intracellular Salmonella Typhimurium Blocks Host Cell Cytokinesis
, Infection and Immunity, Vol: 84, Pages: 2149-2158, ISSN: 1098-5522Several bacterial pathogens and viruses interfere with the cell cycle of their host cells to enhance virulence. This is especially apparent in bacteria that colonise the gut epithelium, where inhibition of the cell cycle of infected cells enhances the intestinal colonisation. We found that intracellular Salmonella enterica Typhimurium induced the binucleation of a large proportion of epithelial cells by 14 hours post invasion, which was dependent on an intact Salmonella pathogenicity island-2 (SPI-2) type 3 secretion system. The SPI-2 effectors SseF and SseG were required to induce binucleation. SseF and SseG are known to maintain microcolonies of Salmonella-containing vacuoles close to the microtubule organising centre of infected epithelial cells. During host cell division these clustered microcolonies prevented the correct localisation of members of the chromosomal passenger complex and mitotic kinesin-like protein 1, and consequently prevented cytokinesis. Tetraploidy, arising from a cytokinesis defect, is known to have a deleterious effect on subsequent cell divisions, either resulting in chromosomal instabilities or cell cycle arrest. In infected mice, proliferation of small intestinal epithelial cells was compromised in an SseF/SseG-dependent manner, suggesting that cytokinesis failure caused by S. Typhimurium delays epithelial cell turnover in the intestine.
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Journal articleLund-Palau H, Turnbull AR, Bush A, et al., 2016,
Pseudomonas aeruginosa infection in cystic fibrosis: pathophysiological mechanisms and therapeutic approaches
, Expert Review of Respiratory Medicine, Vol: 10, Pages: 685-697, ISSN: 1747-6348Pseudomonas aeruginosa is a remarkably versatile environmental bacterium with an extraordinary capacity to infect the cystic fibrosis (CF) lung. Infection with P. aeruginosa occurs early, and although eradication can be achieved following early detection, chronic infection occurs in over 60% of adults with CF. Chronic infection is associated with accelerated disease progression and increased mortality. Extensive research has revealed complex mechanisms by which P. aeruginosa adapts to and persists within the CF airway. Yet knowledge gaps remain, and prevention and treatment strategies are limited by the lack of sensitive detection methods and by a narrow armoury of antibiotics. Further developments in this field are urgently needed in order to improve morbidity and mortality in people with CF. Here, we summarize current knowledge of pathophysiological mechanisms underlying P. aeruginosa infection in CF. Established treatments are discussed, and an overview is offered of novel detection methods and therapeutic strategies in development.
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