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Journal articleKlionsky DJ, Abdelmohsen K, Abe A, et al., 2016,
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
, Autophagy, Vol: 12, Pages: 1-215, ISSN: 1554-8635 -
Journal articleLeen EN, Sorgeloos F, Correia S, et al., 2016,
A conserved interaction between a C-terminal motif in norovirus VPg and the HEAT-1 domain of eIF4G is essential for translation initiation
, PLOS Pathogens, Vol: 12, ISSN: 1553-7366Translation initiation is a critical early step in the replication cycle of the positive-sense, single-stranded RNA genome of noroviruses, a major cause of gastroenteritis in humans. Norovirus RNA, which has neither a 5´ m7G cap nor an internal ribosome entry site (IRES), adopts an unusual mechanism to initiate protein synthesis that relies on interactions between the VPg protein covalently attached to the 5´-end of the viral RNA and eukaryotic initiation factors (eIFs) in the host cell. For murine norovirus (MNV) we previously showed that VPg binds to the middle fragment of eIF4G (4GM; residues 652-1132). Here we have used pull-down assays, fluorescence anisotropy, and isothermal titration calorimetry (ITC) to demonstrate that a stretch of ~20 amino acids at the C terminus of MNV VPg mediates direct and specific binding to the HEAT-1 domain within the 4GM fragment of eIF4G. Our analysis further reveals that the MNV C terminus binds to eIF4G HEAT-1 via a motif that is conserved in all known noroviruses. Fine mutagenic mapping suggests that the MNV VPg C terminus may interact with eIF4G in a helical conformation. NMR spectroscopy was used to define the VPg binding site on eIF4G HEAT-1, which was confirmed by mutagenesis and binding assays. We have found that this site is non-overlapping with the binding site for eIF4A on eIF4G HEAT-1 by demonstrating that norovirus VPg can form ternary VPg-eIF4G-eIF4A complexes. The functional significance of the VPg-eIF4G interaction was shown by the ability of fusion proteins containing the C-terminal peptide of MNV VPg to inhibit in vitro translation of norovirus RNA but not cap- or IRES-dependent translation. These observations define important structural details of a functional interaction between norovirus VPg and eIF4G and reveal a binding interface that might be exploited as a target for antiviral therapy.
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Journal articleComas I, Hailu E, Kiros T, et al., 2015,
Population Genomics of Mycobacterium tuberculosis in Ethiopia Contradicts the Virgin Soil Hypothesis for Human Tuberculosis in Sub-Saharan Africa
, Current Biology, Vol: 25, Pages: 3260-3266, ISSN: 1879-0445Colonial medical reports claimed that tuberculosis (TB) was largely unknown in Africa prior to European contact, providing a “virgin soil” for spread of TB in highly susceptible populations previously unexposed to the disease [1 and 2]. This is in direct contrast to recent phylogenetic models which support an African origin for TB [3, 4, 5 and 6]. To address this apparent contradiction, we performed a broad genomic sampling of Mycobacterium tuberculosis in Ethiopia. All members of the M. tuberculosis complex (MTBC) arose from clonal expansion of a single common ancestor [ 7] with a proposed origin in East Africa [ 3, 4 and 8]. Consistent with this proposal, MTBC lineage 7 is almost exclusively found in that region [ 9, 10 and 11]. Although a detailed medical history of Ethiopia supports the view that TB was rare until the 20th century [12], over the last century Ethiopia has become a high-burden TB country [13]. Our results provide further support for an African origin for TB, with some genotypes already present on the continent well before European contact. Phylogenetic analyses reveal a pattern of serial introductions of multiple genotypes into Ethiopia in association with human migration and trade. In place of a “virgin soil” fostering the spread of TB in a previously naive population, we propose that increased TB mortality in Africa was driven by the introduction of European strains of M. tuberculosis alongside expansion of selected indigenous strains having biological characteristics that carry a fitness benefit in the urbanized settings of post-colonial Africa.
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Journal articleFairweather NF, Willing SE, Richards EJ, et al., 2015,
Increased toxin expression in a Clostridium difficile mfd mutant
, BMC Microbiology, ISSN: 1471-2180 -
Journal articleWong CT, Xu Y, Gupta A, et al., 2015,
Structural analysis of haemoglobin binding by HpuA from the Neisseriaceae family
, Nature Communications, Vol: 6, ISSN: 2041-1723The Neisseriaceae family of bacteria causes a range of diseases including meningitis, septicaemia, gonorrhoea and endocarditis, and extracts haem from haemoglobin as an important iron source within the iron-limited environment of its human host. Herein we report crystal structures of apo- and haemoglobin-bound HpuA, an essential component of this haem import system. The interface involves long loops on the bacterial receptor that present hydrophobic side chains for packing against the surface of haemoglobin. Interestingly, our structural and biochemical analyses of Kingella denitrificans and Neisseria gonorrhoeae HpuA mutants, although validating the interactions observed in the crystal structure, show how Neisseriaceae have the fascinating ability to diversify functional sequences and yet retain the haemoglobin binding function. Our results present the first description of HpuA’s role in direct binding of haemoglobin.
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Journal articleLarrouy-Maumus GJ, Abigail Clements, Alain Filloux, et al., 2015,
Direct detection of lipid A on intact Gram-negative bacteria byMALDI-TOF mass spectrometry
, Journal of Microbiological Methods, Vol: 120, Pages: 68-71, ISSN: 1872-8359The purification and characterization of Gram-negative bacterial lipid A is tedious and time-consuming. Herein we report a rapid and sensitive method to identify lipid A directly on intact bacteria without any chemical treatment or purification, using an atypical solvent system to solubilize the matrix combined with MALDI-TOF mass spectrometry.
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Conference paperShah A, Kannambath S, Herbst S, et al., 2015,
'THE KISS OF DEATH' - CALCINEURIN INHIBITORS PREVENT ACTIN-DEPENDENT LATERAL TRANSFER OF ASPERGILLUS FUMIGATUS IN NECROPTOTIC HUMAN MACROPHAGES
, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A48-A48, ISSN: 0040-6376 -
Journal articleFigueira R, Brown DR, Ferreira D, et al., 2015,
Adaptation to sustained nitrogen starvation by Escherichia coli requires the eukaryote-like serine/ threonine kinase YeaG
, Scientific Reports, Vol: 5, ISSN: 2045-2322 -
Journal articleWitcomb LA, Collins JW, McCarthy AJ, et al., 2015,
Bioluminescent Imaging Reveals Novel Patterns of Colonization and Invasion in Systemic Escherichia coli K1 Experimental Infection in the Neonatal Rat
, Infection and Immunity, Vol: 83, Pages: 4528-4540, ISSN: 0019-9567Key features of Escherichia coli K1-mediated neonatal sepsis and meningitis, such as a strong age dependency and development along the gut-mesentery-blood-brain course of infection, can be replicated in the newborn rat. We examined temporal and spatial aspects of E. coli K1 infection following initiation of gastrointestinal colonization in 2-day-old (P2) rats after oral administration of E. coli K1 strain A192PP and a virulent bioluminescent derivative, E. coli A192PP-lux2. A combination of bacterial enumeration in the major organs, two-dimensional bioluminescence imaging, and three-dimensional diffuse light imaging tomography with integrated micro-computed tomography indicated multiple sites of colonization within the alimentary canal; these included the tongue, esophagus, and stomach in addition to the small intestine and colon. After invasion of the blood compartment, the bacteria entered the central nervous system, with restricted colonization of the brain, and also invaded the major organs, in line with increases in the severity of symptoms of infection. Both keratinized and nonkeratinized surfaces of esophagi were colonized to a considerably greater extent in susceptible P2 neonates than in corresponding tissues from infection-resistant 9-day-old rat pups; the bacteria appeared to damage and penetrate the nonkeratinized esophageal epithelium of infection-susceptible P2 animals, suggesting the esophagus represents a portal of entry for E. coli K1 into the systemic circulation. Thus, multimodality imaging of experimental systemic infections in real time indicates complex dynamic patterns of colonization and dissemination that provide new insights into the E. coli K1 infection of the neonatal rat.
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Journal articlefilloux A, wood TE, Hachani A, 2015,
Type VI secretion and anti-host effectors.
, Current Opinion in Microbiology, ISSN: 1879-0364
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