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Journal articlePatel DF, Peiro T, Bruno N, et al., 2019,
Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte-dendritic cell antigen presentation
, Science Immunology, Vol: 4, Pages: 1-18, ISSN: 2470-9468Neutrophil mobilization, recruitmentand clearancemust be tightly regulated asover-exuberant neutrophilic inflammation isimplicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophilstherapeutically have failed to consider theirpleiotropic functions and theimplications of disrupting fundamental regulatory pathways that govern their turnover duringhomeostasisand inflammation.Using thehouse dust mite(HDM)model of allergic airways disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated TH2 inflammation, epithelial remodelling and airway resistance. Mechanistically, this was attributable to astriking increase insystemic G-CSF concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increasedG-CSF augmented allergic sensitization in HDM exposed animals bydirectly acting on airway ILC2s toelicitcytokine production.Moreover, increased systemic G-CSF promoted expansion of bone marrow monocyte progenitor populations, which resulted in enhanced antigen presentation by an augmented peripheral monocyte-derived dendritic cell pool.By modelling the effects of neutrophil depletion, our studies have therefore uncovered previously unappreciated roles for G-CSF in modulating ILC2 function and antigen presentation. More broadly,they highlight an unexpected regulatory role for neutrophils in limiting TH2 allergic airway inflammation.
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Journal articleClarke R, Bruderer M, Ha KP, et al., 2019,
RexAB is essential for the mutagenic repair of Staphylococcus aureus DNA damage caused by co-trimoxazole
, Antimicrobial Agents and Chemotherapy, Vol: 63, ISSN: 0066-4804Co-trimoxazole (SXT) is a combination therapeutic that consists of sulfamethoxazole and trimethoprim that is increasingly used to treat skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, the use of SXT is limited to the treatment of low-burden, superficial S. aureus infections and its therapeutic value is compromised by the frequent emergence of resistance. As a first step towards the identification of approaches to enhance the efficacy of SXT, we examined the role of bacterial DNA repair in antibiotic susceptibility and mutagenesis. We found that mutants lacking the DNA repair complex RexAB had a modest 2-fold lower SXT MIC than wild-type strains but were killed 50-5000-fold more efficiently by the combination antibiotic at the breakpoint concentration. SXT-mediated DNA damage occurred via both thymidine limitation and the generation of reactive oxygen species, and triggered induction of the SOS response in a RexAB-dependent manner. SOS induction was associated with a 50% increase in the mutation rate, which may contribute to emergence of resistant strains during SXT therapy. In summary, this work determined that SXT caused DNA damage in S. aureus via both thymidine limitation and oxidative stress, which was repaired by the RexAB complex, leading to induction of the mutagenic SOS response. Small molecule inhibitors of RexAB could therefore have therapeutic value by increasing the efficacy of SXT and decreasing the emergence of drug-resistance during treatment of infections caused by S. aureus.
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Journal articleWang R, Kreutzfeldt K, Botella H, et al., 2019,
Persistent mycobacterium tuberculosis infection in mice requires PerM for successful cell division
, eLife, Vol: 8, Pages: 1-21, ISSN: 2050-084XThe ability of Mycobacterium tuberculosis (Mtb) to persist in its host is central to thepathogenesis of tuberculosis, yet the underlying mechanisms remain incompletely defined. PerM,an integral membrane protein, is required for persistence of Mtb in mice. Here, we show that perMdeletion caused a cell division defect specifically during the chronic phase of mouse infection, butdid not affect Mtb’s cell replication during acute infection. We further demonstrate that PerM isrequired for cell division in chronically infected mice and in vitro under host-relevant stressesbecause it is part of the mycobacterial divisome and stabilizes the essential divisome protein FtsB.These data highlight the importance of sustained cell division for Mtb persistence, define conditionspecific requirements for cell division and reveal that survival of Mtb during chronic infectiondepends on a persistence divisome.
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Journal articleAsai M, Li Y, Singh Khara J, et al., 2019,
Galleria mellonella: a novel infection model for screening potential anti-mycobacterial compounds against members of the Mycobacterium tuberculosis complex
, Frontiers in Microbiology, Vol: 10, ISSN: 1664-302XDrug screening models have a vital role in the development of novel antimycobacterial agents which are urgently needed to tackle drug-resistant tuberculosis (TB). We recently established the larvae of the insect Galleria mellonella (greater wax moth) as a novel infection model for the Mycobacterium tuberculosis complex. Here we demonstrate its use as a rapid and reproducible screen to evaluate antimycobacterial drug efficacy using larvae infected with bioluminescent Mycobacterium bovis BCG lux. Treatment improved larval survival outcome and, with the exception of pyrazinamide, was associated with a significant reduction in in vivo mycobacterial bioluminescence over a 96 hour period compared to the untreated controls. Isoniazid and rifampicin displayed the greatest in vivo efficacy and survival outcome. Thus G. mellonella, infected with bioluminescent mycobacteria, can rapidly determine in vivo drug efficacy, and has the potential to significantly reduce and/or replace the number of animals used in TB research.
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Book chapterHill P, Helaine S, 2019,
Antibiotic Persisters and Relapsing Salmonella enterica Infections.
, Persister Cells and Infectious Disease, Editors: Lewis, Publisher: Springer Nature, ISBN: 9783030252410Antibiotic persistence is defined as the ability of a subpopulation of bacteria within a clonal antibiotic-susceptible population to survive antibiotic treatment. Studies on antibiotic persistence have traditionally been carried out on bacteria cultured in laboratory media. However, over recent years, there has been a push to study antibiotic persisters in more physiologically relevant systems. Thus, the concept of antibiotic persistence during infection, which refers to the ability of a subpopulation of bacteria to survive combined host and antibiotic challenges, has emerged as a major new frontier of research. Here, we discuss the relevance and principles of this concept using relapsing Salmonella enterica infections as an example. We critically evaluate the clinical and experimental evidence for the existence and importance of antibiotic persisters in relapsing Salmonella infections; we outline our current understanding of the molecular mechanisms that enable successful antibiotic persistence during infection; and, finally, we discuss the challenges for this nascent field going forward.
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Journal articleMurphy P, Xu Y, Rouse SL, et al., 2019,
Functional 3D architecture in an intrinsically disordered E3 ligase domain facilitates ubiquitin transfer
<jats:title>Abstract</jats:title><jats:p>Post-translational modification of proteins with ubiquitin represents a widely used mechanism for cellular regulation. Ubiquitin is activated by an E1 enzyme, transferred to an E2 conjugating enzyme and covalently linked to substrates by one of an estimated 600 E3 ligases (1). RING E3 ligases play a pivotal role in selecting substrates and priming the ubiquitin loaded E2 (E2~Ub) for catalysis (2,3). RING E3 RNF4 is a SUMO targeted ubiquitin ligase (4) with important roles in arsenic therapy for cancer (4,5) and in DNA damage responses (6,7). RNF4 has a RING domain and a substrate recognition domain containing multiple SUMO Interaction Motifs (SIM<jats:sc>s</jats:sc>) embedded in a region thought to be intrinsically disordered (8). While molecular details of SUMO recognition by the SIMs (8–10) and RING engagement of ubiquitin loaded E2 (3,11–15) have been determined, the mechanism by which SUMO substrate is delivered to the RING to facilitate ubiquitin transfer is an important question to be answered. Here, we show that the intrinsically disordered substrate-recognition domain of RNF4 maintains the SIMs in a compact global architecture that facilitates SUMO binding, while a highly-basic region positions substrate for nucleophilic attack on RING-bound ubiquitin loaded E2. Contrary to our expectation that the substrate recognition domain of RNF4 was completely disordered, distance measurements using single molecule Fluorescence Resonance Energy Transfer (smFRET) and NMR paramagnetic relaxation enhancement (PRE) revealed that it adopts a defined conformation primed for SUMO interaction. Mutational and biochemical analysis indicated that electrostatic interactions involving the highly basic region linking the substrate recognition and RING domains juxtaposed those regions and mediated substrate ubiquitination. Our results offer insight into a key step in substrate ubiquitination by a membe
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Journal articleMullineaux-Sanders C, Sanchez-Garrido J, Hopkins EGD, et al., 2019,
Citrobacter rodentium-host-microbiota interactions: immunity, bioenergetics and metabolism
, NATURE REVIEWS MICROBIOLOGY, Vol: 17, Pages: 701-715, ISSN: 1740-1526- Author Web Link
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- Citations: 48
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Journal articleGonzalez D, Mavridou D, 2019,
Making the best of aggression, the many dimensions of bacterial toxin regulation
, Trends in Microbiology, Vol: 27, Pages: 897-905, ISSN: 0966-842XMost bacteria use toxins to exclude competitors.As the synthesis and delivery of these moleculesentail considerablecostsfor the producers, theirexpressionis tightly regulated, often by molecular systems detecting physiological stressesor environment-specific cues.However, the ecological connection between such systemsand competitive behaviorsis not always clear. Here, we review the regulation of antibacterial toxins and propose a conceptual framework organizing the decision-making processes controlling toxin production. As bacteria are unable to precisely identify their competitors,we argue that toxin regulation primarily responds to cues directly or indirectly associated with the presence of competing strains. The density and fitnessof the producing populational so play a role in the decision-making process.Overall, we contendthat optimal toxin production strategies involvemonitoring of both self and foe.
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Journal articleCerny O, Holden D, 2019,
Salmonella SPI-2 type III secretion system-dependent inhibition of antigen presentation and T cell function
, Immunology Letters, Vol: 215, Pages: 35-39, ISSN: 0165-2478Salmonella enterica serovars infect a broad range of mammalian hosts, including humans, causing both gastrointestinal and systemic diseases. Effective immune responses to Salmonella infections depend largely on CD4+ T cell activation by dendritic cells (DCs). Bacteria are internalised by intestinal DCs and respond by translocating effectors of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (T3SS) into host cells. In this review, we discuss processes that are hijacked by SPI-2 T3SS effectors and how this affects DC biology and the activation of T cell responses.
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Journal articleBacigalupe R, Angeles Tormo-Mas M, Penades JR, et al., 2019,
A multihost bacterial pathogen overcomes continuous population bottlenecks to adapt to new host species
, Science Advances, Vol: 5, ISSN: 2375-2548While many bacterial pathogens are restricted to single host species, some have the capacity to undergo host switches, leading to the emergence of new clones that are a threat to human and animal health. However, the bacterial traits that underpin a multihost ecology are not well understood. Following transmission to a new host, bacterial populations are influenced by powerful forces such as genetic drift that reduce the fixation rate of beneficial mutations, limiting the capacity for host adaptation. Here, we implement a novel experimental model of bacterial host switching to investigate the ability of the multihost pathogen Staphylococcus aureus to adapt to new species under continuous population bottlenecks. We demonstrate that beneficial mutations accumulated during infection can overcome genetic drift and sweep through the population, leading to host adaptation. Our findings highlight the remarkable capacity of some bacteria to adapt to distinct host niches in the face of powerful antagonistic population forces.
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