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Chemokines have been shown to be effective bactericidal molecules against a variety of bacteria and fungi in vitro. These direct antimicrobial effects are independent of their chemotactic activities involving immunological receptors. However, the direct biological role that these proteins may play in host defense, particularly against intestinal pathogens, is poorly understood. Here, we show that CXCL9, an ELR- chemokine, exhibits direct antimicrobial activity against Citrobacter rodentium, an attaching/effacing pathogen that infects the gut mucosa. Inhibition of this antimicrobial activity in vivo using anti-CXCL9 antibodies increases host susceptibility to C. rodentium infection with pronounced bacterial penetration into crypts, increased bacterial load, and worsened tissue pathology. Using Rag1(-/-) mice and CXCR3(-/-) mice, we demonstrate that the role for CXCL9 in protecting the gut mucosa is independent of an adaptive response or its immunological receptor, CXCR3. Finally, we provide evidence that phagocytes function in tandem with NK cells for robust CXCL9 responses to C. rodentium. These findings identify a novel role for the immune cell-derived CXCL9 chemokine in directing a protective antimicrobial response in the intestinal mucosa.

Bacterial pathogens often manipulate host immune pathways to establish acute and chronic infection. Many Gram-negative bacteria do this by secreting effector proteins through a type III secretion system that alter the host response to the pathogen. In this study, we determined that the phage-encoded GogB effector protein in Salmonella targets the host SCF E3 type ubiquitin ligase through an interaction with Skp1 and the human F-box only 22 (FBXO22) protein. Domain mapping and functional knockdown studies indicated that GogB-containing bacteria inhibited IκB degradation and NFκB activation in macrophages, which required Skp1 and a eukaryotic-like F-box motif in the C-terminal domain of GogB. GogB-deficient Salmonella were unable to limit NFκB activation, which lead to increased proinflammatory responses in infected mice accompanied by extensive tissue damage and enhanced colonization in the gut during long-term chronic infections. We conclude that GogB is an anti-inflammatory effector that helps regulate inflammation-enhanced colonization by limiting tissue damage during infection.

The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The acquisition of metallo-β-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenem-resistant Gram-negative pathogens that threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. To date, a clinical inhibitor of MBLs that could reverse resistance and re-sensitize resistant Gram-negative pathogens to carbapenems has not been found. Here we have identified a fungal natural product, aspergillomarasmine A (AMA), that is a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM or NDM-type alleles. In mice infected with NDM-1-expressing Klebsiella pneumoniae , AMA efficiently restored meropenem activity, demonstrating that a combination of AMA and a carbapenem antibiotic has therapeutic potential to address the clinical challenge of MBL-positive carbapenem-resistant Gram-negative pathogens. The emergence of Gram-negative pathogens resistant to carbapenem antibiotics is a global health concern and carbapenem resistance often arises through acquisition of β-lactamase enzymes; this study identifies the natural fungal product aspergillomarasmine A as a metallo-β-lactamase inhibitor and a potential treatment to tackle carbapenem resistance. A natural adjuvant for β-lactam antibiotics Infection with Gram-negative pathogens bearing metallo-β-lactamases such as NDM-1 and VIM is a growing public health problem and threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. Here, Gerard Wright and colleagues report a screen for naturally produced inhibitors of NDM-1 in an extensive collection of DMSO-dissolved natural product extracts derived from environmental microorganisms. One extract (from Aspergillus versicolor ) exhibited a particularly potent anti-NDM-1 activity and was identified as aspergillomarasmine A (AMA), a natural product first reported some 50 years ago associated with leaf wilting. AMA is a rapid and potent inhibitor of both NDM-1 and VIM-2, and the authors find that AMA fully restores antibiotic efficacy in vitro and in vivo against bacterial pathogens possessing either VIM- or NDM-type resistance genes. AMA is non-toxic and well tolerated, making it a realistic prospect as an antibiotic adjuvant.

Neutrophils engulf and kill bacteria using oxidative and nonoxidative mechanisms. Despite robust antimicrobial activity, neutrophils are impaired in directing Salmonella clearance and harbor viable intracellular bacteria during early stages of infection that can subsequently escape to more-permissive cell types. The mechanisms accounting for this immune impairment are not understood. We report that Salmonella limits exposure to oxidative damage elicited by d -amino acid oxidase (DAO) in neutrophils by expressing an ABC importer specific for d -alanine, a DAO substrate found in peptidoglycan stem peptides. A Salmonella dalS mutant defective for d -alanine import was more susceptible to killing by DAO through exposure to greater oxidative stress during infection. This fitness defect was reversed by selective depletion of neutrophils or by inhibition of DAO in vivo with a small-molecule inhibitor. DalS-mediated subversion of neutrophil DAO is a novel host-pathogen interaction that enhances Salmonella survival during systemic infection. IMPORTANCE Neutrophils engulf Salmonella during early stages of infection, but bacterial killing is incomplete. Very little is known about how Salmonella survives in neutrophils to gain access to other cell types during infection. In this study, we show that d -amino acid oxidase (DAO) in neutrophils consumes d -alanine and that importing this substrate protects Salmonella from oxidative killing by neutrophil DAO. Loss of this importer results in increased bacterial killing in vitro , in neutrophils, and in a mouse model of infection, all phenotypes that are lost upon inhibition of DAO. These findings add mechanistic insight into a novel host-pathogen interaction that has consequences on infection outcome. Neutrophils engulf Salmonella during early stages of infection, but bacterial killing is incomplete. Very little is known about how Salmonella survives in neutrophils to gain access to other cell types during infection. In this study, we show that d -amino acid oxidase (DAO) in neutrophils consumes d -alanine and that importing this substrate protects Salmonella from oxidative killing by neutrophil DAO. Loss of this importer results in increased bacterial killing in vitro , in neutrophils, and in a mouse model of infection, all phenotypes that are lost upon inhibition of DAO. These findings add mechanistic insight into a novel host-pathogen interaction that has consequences on infection outcome.

Crohn’s disease is a chronic inflammatory condition of the gastrointestinal tract in which alterations to the bacterial community contribute to disease. Adherent-invasive Escherichia coli are associated with human Crohn’s disease; however, their role in intestinal immunopathology is unclear because of the lack of an animal model compatible with chronic timescales. Here we establish chronic adherent-invasive Escherichia coli infection in streptomycin-treated conventional mice (CD1, DBA/2, C3H, 129e and C57BL/6), enabling the study of host response and immunopathology. Adherent-invasive Escherichia coli induces an active T-helper 17 response, heightened levels of proinflammatory cytokines and fibrotic growth factors, with transmural inflammation and fibrosis. Depletion of CD8+ T cells increases caecal bacterial load, pathology and intestinal fibrosis in C57BL/6 mice, suggesting a protective role. Our findings provide evidence that chronic adherent-invasive Escherichia coli infections result in immunopathology similar to that seen in Crohn’s disease. With this model, research into the host and bacterial genetics associated with adherent-invasive Escherichia coli -induced disease becomes more widely accessible. Intestinal infection with adherent-invasive Escherichia coli is associated with Crohn’s disease in humans; however, its functional role remains unclear, in part due to a lack of animal models, which sustain chronic disease. Here the authors establish such a model in mice and show that it shares features with human Crohn’s disease.

Chemokines have been shown to be effective bactericidal molecules against a variety of bacteria and fungi in vitro. These direct antimicrobial effects are independent of their chemotactic activities involving immunological receptors. However, the direct biological role that these proteins may play in host defense, particularly against intestinal pathogens, is poorly understood. Here, we show that CXCL9, an ELR- chemokine, exhibits direct antimicrobial activity against Citrobacter rodentium, an attaching/effacing pathogen that infects the gut mucosa. Inhibition of this antimicrobial activity in vivo using anti-CXCL9 antibodies increases host susceptibility to C. rodentium infection with pronounced bacterial penetration into crypts, increased bacterial load, and worsened tissue pathology. Using Rag1-/- mice and CXCR3-/- mice, we demonstrate that the role for CXCL9 in protecting the gut mucosa is independent of an adaptive response or its immunological receptor, CXCR3. Finally, we provide evidence that phagocytes function in tandem with NK cells for robust CXCL9 responses to C. rodentium. These findings identify a novel role for the immune cell-derived CXCL9 chemokine in directing a protective antimicrobial response in the intestinal mucosa.

The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The acquisition of metallo-β-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenem-resistant Gram-negative pathogens that threatens the use of penicillin, cephalosporin, and carbapenem antibiotics to treat infections. So far a clinical inhibitor of MBLs that could reverse resistance and re-sensitize resistant Gram-negative pathogens to carbapenems does not exist. Here we have identified a fungal natural product, aspergillomarasmine A (AMA) that is a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM or NDM-type alleles. In mice infected with NDM-1-expressing Klebsiella pneumoniae, AMA efficiently restored meropenem activity, demonstrating that a combination of AMA and a carbapenem antibiotic has therapeutic potential to address the clinical challenge of MBL positive carbapenem-resistant Gram-negative pathogens.

The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The acquisition of metallo-β-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenem-resistant Gram-negative pathogens that threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. To date, a clinical inhibitor of MBLs that could reverse resistance and re-sensitize resistant Gram-negative pathogens to carbapenems has not been found. Here we have identified a fungal natural product, aspergillomarasmine A (AMA), that is a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM or NDM-typealleles. In mice infected with NDM-1-expressing Klebsiella pneumoniae, AMA efficiently restored meropenem activity, demonstrating that a combination of AMA and a carbapenem antibiotic has therapeutic potential to address the clinical challenge of MBL-positive carbapenem-resistant Gram-negative pathogens.