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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 -
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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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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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 articlePakharukova N, Garnett JA, Tuittila M, et al., 2015,
Structural Insight into Archaic and Alternative Chaperone-Usher Pathways Reveals a Novel Mechanism of Pilus Biogenesis.
, PLOS Pathogens, Vol: 11, ISSN: 1553-7366Gram-negative pathogens express fibrous adhesive organelles that mediate targeting to sites of infection. The major class of these organelles is assembled via the classical, alternative and archaic chaperone-usher pathways. Although non-classical systems share a wider phylogenetic distribution and are associated with a range of diseases, little is known about their assembly mechanisms. Here we report atomic-resolution insight into the structure and biogenesis of Acinetobacter baumannii Csu and Escherichia coli ECP biofilm-mediating pili. We show that the two non-classical systems are structurally related, but their assembly mechanism is strikingly different from the classical assembly pathway. Non-classical chaperones, unlike their classical counterparts, maintain subunits in a substantially disordered conformational state, akin to a molten globule. This is achieved by a unique binding mechanism involving the register-shifted donor strand complementation and a different subunit carboxylate anchor. The subunit lacks the classical pre-folded initiation site for donor strand exchange, suggesting that recognition of its exposed hydrophobic core starts the assembly process and provides fresh inspiration for the design of inhibitors targeting chaperone-usher systems.
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Journal articleCharlton T, Kovacs-Simon A, Michell S, et al., 2015,
Quantitative lipoproteomics in Clostridium difficile reveals a role for lipoproteins in sporulation
, Chemistry & Biology, Vol: 22, ISSN: 1074-5521Bacterial lipoproteins are surface exposed, anchored to the membrane by Sdiacylglyceryl modification of the N-terminal cysteine thiol. They play important roles inmany essential cellular processes and in bacterial pathogenesis. For example,Clostridium difficile is a Gram-positive anaerobe that causes severe gastrointestinaldisease, however, its lipoproteome remains poorly characterized. Here we describe theapplication of metabolic tagging with alkyne-tagged lipid analogues, in combinationwith quantitative proteomics, to profile protein lipidation across diverse C. difficilestrains and on inactivation of specific components of the lipoprotein biogenesispathway. These studies provide the first comprehensive map of the C. difficilelipoproteome, demonstrate the existence of two active lipoprotein signal peptidasesand provide insights into lipoprotein function, implicating the lipoproteome intransmission of this pathogen.
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