Publications
Results
- Showing results for:
- Reset all filters
Search results
-
Journal articleImbert PRC, Louche A, Luizet J-B, et al., 2017,
A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors
, EMBO JOURNAL, Vol: 36, Pages: 1869-1887, ISSN: 0261-4189 -
Journal articlePallett MA, Crepin VF, Serafini N, et al., 2017,
Bacterial virulence factor inhibits caspase-4/11 activation in intestinal epithelial cells
, Mucosal Immunology, Vol: 10, Pages: 602-612, ISSN: 1935-3456The human pathogen enteropathogenic Escherichia coli (EPEC), as well as the mouse pathogen Citrobacter rodentium, colonize the gut mucosa via attaching and effacing lesion formation and cause diarrheal diseases. EPEC and C. rodentium type III secretion system (T3SS) effectors repress innate immune responses and infiltration of immune cells. Inflammatory caspases such as caspase-1 and caspase-4/11 are crucial mediators of host defense and inflammation in the gut via their ability to process cytokines such as interleukin (IL)-1β and IL-18. Here we report that the effector NleF binds the catalytic domain of caspase-4 and inhibits its proteolytic activity. Following infection of intestinal epithelial cells (IECs) EPEC inhibited caspase-4 and IL-18 processing in an NleF-dependent manner. Depletion of caspase-4 in IECs prevented the secretion of mature IL-18 in response to infection with EPECΔnleF. NleF-dependent inhibition of caspase-11 in colons of mice prevented IL-18 secretion and neutrophil influx at early stages of C. rodentium infection. Neither wild-type C. rodentium nor C. rodentiumΔnleF triggered neutrophil infiltration or IL-18 secretion in Cas11 or Casp1/11-deficient mice. Thus, IECs have a key role in modulating early innate immune responses in the gut via a caspase-4/11—IL-18 axis, which is targeted by virulence factors encoded by enteric pathogens.
-
Journal articleKhara JS, Obuobi S, Wang Y, et al., 2017,
Disruption of drug-resistant biofilms using de novo designed short α-helicalantimicrobial peptides with idealized facial amphiphilicity
, Acta Biomaterialia, Vol: 57, Pages: 103-114, ISSN: 1878-7568The escalating threat of antimicrobial resistance has increased pressure to develop novel therapeutic strategies to tackle drug-resistant infections. Antimicrobial peptides have emerged as a promising class of therapeutics for various systemic and topical clinical applications. In this study, the de novo design of α-helical peptides with idealized facial amphiphilicities, based on an understanding of the pertinent features of protein secondary structures, is presented. Synthetic amphiphiles composed of the backbone sequence (X1Y1Y2X2)n, where X1 and X2 are hydrophobic residues (Leu or Ile or Trp), Y1 and Y2 are cationic residues (Lys), and n is the number repeat units (2 or 2.5 or 3), demonstrated potent broad-spectrum antimicrobial activities against clinical isolates of drug-susceptible and multi-drug resistant bacteria. Live-cell imaging revealed that the most selective peptide, (LKKL)3, promoted rapid permeabilization of bacterial membranes. Importantly, (LKKL)3 not only suppressed biofilm growth, but effectively disrupted mature biofilms after only 2 h of treatment. The peptides (LKKL)3 and (WKKW)3 suppressed the production of LPS-induced pro-inflammatory mediators to levels of unstimulated controls at low micromolar concentrations. Thus, the rational design strategies proposed herein can be implemented to develop potent, selective and multifunctional α-helical peptides to eradicate drug-resistant biofilm-associated infections.
-
Journal articleLiew N, Mazon Moya MJ, Wierzbicki CJ, et al., 2017,
Chytrid fungus infection in zebrafish demonstrates that the pathogen can parasitize non-amphibian vertebrate hosts
, Nature Communications, Vol: 8, ISSN: 2041-1723Aquatic chytrid fungi threaten amphibian biodiversity worldwide owing to their ability to rapidly expand their geographical distributions and to infect a wide range of hosts. Combating this risk requires an understanding of chytrid host range to identify potential reservoirs of infection and to safeguard uninfected regions through enhanced biosecurity. Here we extend our knowledge on the host range of the chytrid Batrachochytrium dendrobatidis by demonstrating infection of a non-amphibian vertebrate host, the zebrafish. We observe dose-dependent mortality and show that chytrid can infect and proliferate on zebrafish tissue. We also show that infection phenotypes (fin erosion, cell apoptosis and muscle degeneration) are direct symptoms of infection. Successful infection is dependent on disrupting the zebrafish microbiome, highlighting that, as is widely found in amphibians, commensal bacteria confer protection against this pathogen. Collectively, our findings greatly expand the limited tool kit available to study pathogenesis and host response to chytrid infection.
-
Journal articleHall A, Gollan B, Helaine S, 2017,
Toxin-antitoxin systems: reversible toxicity
, Current Opinion in Microbiology, Vol: 36, Pages: 102-110, ISSN: 1879-0364Toxin–antitoxin (TA) systems encoded on the plasmids and chromosomes of bacteria are emerging as key players in stress adaptation. In particular, they have been implicated in the induction of persisters non-growing cells that can evade antibiotic exposure. TA toxins operate by a diverse range of mechanisms, either destructive or conservative, leading to the reversible growth arrest of bacterial cells. Whilst the molecular mechanisms of intoxication are now well understood, we still have very little information on how corrupted cells reawaken. Alongside the phenomenon of conditional cooperativity, new evidence suggests that the effects of some TA toxins can be reversed, allowing non-growing cells to be detoxified and growth to resume.
-
Journal articlePean CB, Schiebler M, Tan S, et al., 2017,
Regulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection
, Nature Communications, Vol: 8, Pages: 1-11, ISSN: 2041-1723Mycobacterium tuberculosis remains a global threat to human health yet the molecular mechanisms regulating immunity remain poorly understood. Cytokines can promote or inhibit mycobacterial survivalinside macrophages, andthe underlying mechanisms represent potential targets for host-directed therapies. Here we show that cytokine-STAT signaling promotesmycobacterial survivalwithin macrophages by deregulating lipid droplets via ATG2 repression. In Drosophilainfected withMycobacterium marinum,mycobacterium-induced STAT activitytriggered by unpaired-familycytokinesreduces Atg2 expression, permittingderegulation of lipid droplets. Increased Atg2expression, or reduced macrophage triglyceride biosynthesis,normalizes lipid deposition in infected phagocytes and reduces numbersof viable intracellular mycobacteria. In human macrophages,addition ofIL-6promotes mycobacterial survival and BCG-induced lipid accumulation by a similar, but probably not identical, mechanism. Our results reveal Atg2regulation as amechanism by which cytokines can control lipid droplet homeostasis and consequently resistance to mycobacterial infectionin Drosophila.
-
Journal articleMcCarthy RR, Mazon-Moya MJ, Moscoso JA, et al., 2017,
Cyclic-di-GMP regulates lipopolysaccharide modification and contributes to Pseudomonas aeruginosa immune evasion
, Nature Microbiology, Vol: 2, Pages: 1-10, ISSN: 2058-5276Pseudomonas aeruginosa is a Gram-negative bacterial pathogen associated with acute and chronic infections. The universal cyclic-di-GMP second messenger is instrumental in the switch from a motile lifestyle to resilient biofilm as in the cystic fibrosis lung. The SadC diguanylate cyclase is associated with this patho-adaptive transition. Here, we identify an unrecognized SadC partner, WarA, which we show is a methyltransferase in complex with a putative kinase, WarB. We established that WarA binds to cyclic-di-GMP, which potentiates its methyltransferase activity. Together, WarA and WarB have structural similarities with the bifunctional Escherichia coli lipopolysaccharide (LPS) O antigen regulator WbdD. Strikingly, WarA influences P. aeruginosa O antigen modal distribution and interacts with the LPS biogenesis machinery. LPS is known to modulate the immune response in the host, and by using a zebrafish infection model, we implicate WarA in the ability of P. aeruginosa to evade detection by the host.
-
Journal articleDominguez-Huettinger E, Boon NJ, Clarke TB, et al., 2017,
Mathematical Modeling of Streptococcus pneumoniae Colonization, Invasive Infection and Treatment
, FRONTIERS IN PHYSIOLOGY, Vol: 8, ISSN: 1664-042XStreptococcus pneumoniae (Sp) is a commensal bacterium that normally resides on the upper airway epithelium without causing infection. However, factors such as co-infection with influenza virus can impair the complex Sp-host interactions and the subsequent development of many life-threatening infectious and inflammatory diseases, including pneumonia, meningitis or even sepsis. With the increased threat of Sp infection due to the emergence of new antibiotic resistant Sp strains, there is an urgent need for better treatment strategies that effectively prevent progression of disease triggered by Sp infection, minimizing the use of antibiotics. The complexity of the host-pathogen interactions has left the full understanding of underlying mechanisms of Sp-triggered pathogenesis as a challenge, despite its critical importance in the identification of effective treatments. To achieve a systems-level and quantitative understanding of the complex and dynamically-changing host-Sp interactions, here we developed a mechanistic mathematical model describing dynamic interplays between Sp, immune cells, and epithelial tissues, where the host-pathogen interactions initiate. The model serves as a mathematical framework that coherently explains various in vitro and in vitro studies, to which the model parameters were fitted. Our model simulations reproduced the robust homeostatic Sp-host interaction, as well as three qualitatively different pathogenic behaviors: immunological scarring, invasive infection and their combination. Parameter sensitivity and bifurcation analyses of the model identified the processes that are responsible for qualitative transitions from healthy to such pathological behaviors. Our model also predicted that the onset of invasive infection occurs within less than 2 days from transient Sp challenges. This prediction provides arguments in favor of the use of vaccinations, since adaptive immune responses cannot be developed de novo in such a short time. We furthe
-
Journal articleWang S, Lin Y, Todorova N, et al., 2017,
Facet-dependent interactions of islet amyloid polypeptide with gold nanoparti-cles: implications for fibril formation and peptide-induced lipid membrane dis-ruption
, Chemistry of Materials, Vol: 29, ISSN: 1520-5002A comprehensive understanding of the mechanisms of interaction between proteins or peptides and nanomaterials is crucial for the development of nanomaterial-based diagnos-tics and therapeutics. In this work, we systematically explored the interactions between citrate-capped gold nanoparticles (AuNPs) and islet amyloid polypeptide (IAPP), a 37-amino acid peptide hormone co-secreted with insulin from the pancreatic islet. We uti-lized diffusion-ordered spectroscopy, isothermal titration calorimetry, localized surface plasmon resonance spectroscopy, gel electrophoresis, atomic force microscopy, transmis-sion electron microscopy (TEM), and molecular dynamics (MD) simulations to systemati-cally elucidate the underlying mechanism of the IAPP−AuNP interactions. Because of the presence of a metal-binding sequence motif in the hydrophilic peptide domain, IAPP strongly interacts with the Au surface in both the monomeric and fibrillar states. Circular dichroism showed that AuNPs triggered the IAPP conformational transition from random coil to ordered structures (α-helix and β-sheet), and TEM imaging suggested the accelera-tion of IAPP fibrillation in the presence of AuNPs. MD simulations revealed that the IAPP−AuNP interactions were initiated by the N-terminal domain (IAPP residues 1−19), which subsequently induced a facet-dependent conformational change in IAPP. On a Au(111) surface, IAPP was unfolded and adsorbed directly onto the Au surface, while for the Au(100) surface, it interacted predominantly with the citrate adlayer and retained some helical conformation. The observed affinity of AuNPs for IAPP was further applied to reduce the level of peptide-induced lipid membrane disruption.
-
Journal articleLarrouy-Maumus G, Layre E, Clark S, et al., 2017,
Protective efficacy of a lipid antigen vaccine in a guinea pig model of tuberculosis
, VACCINE, Vol: 35, Pages: 1395-1402, ISSN: 0264-410X
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.