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Wallar L.E.,McMaster University | Bysice A.M.,McMaster University | Coombes B.K.,McMaster University | Coombes B.K.,Michael G Degroote Institute For Infectious Disease Research
BMC Microbiology | Year: 2011

Background: Two ancestral nucleoid-associated proteins called Hha and YdgT contribute to the negative regulation of several virulence-associated genes in Salmonella enterica serovar Typhimurium. Our previous work showed that Hha and YdgT proteins are required for negative regulation of Salmonella Pathogenicity Island-2 and that hha ydgT double mutants are attenuated for murine infection. Interestingly, hha ydgT mutant bacteria exhibited a non-motile phenotype suggesting that Hha and YdgT have a role in flagellar regulation. Results: In this study we show that the non-motile phenotype of hha ydgT mutants is due to decreased levels of the master transcriptional regulator FlhD4C 2resulting in down-regulation of class II/III and class III flagellar promoters and lack of surface flagella on these cells. The horizontally acquired pefI-srgD region was found to be partially responsible for this phenotype since deletion of pefI-srgD in a hha ydgT deletion background resulted in transient restoration of class II/III and III transcription, expression of surface flagella, and motility in the quadruple mutant. Conclusion: These data extend our current understanding of the mechanisms through which Hha and YdgT regulate flagellar biosynthesis and further describe how S. Typhimurium has integrated horizontal gene acquisitions into ancestral regulatory networks. © 2011 Wallar et al; licensee BioMed Central Ltd. Source

Tuinema B.R.,McMaster University | Reid-Yu S.A.,McMaster University | Coombes B.K.,McMaster University | Coombes B.K.,Michael G Degroote Institute For Infectious Disease Research
mBio | Year: 2014

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. © 2014 Tuinema et al. Source

Oberc A.,McMaster University | Oberc A.,Michael G Degroote Institute For Infectious Disease Research | Coombes B.K.,McMaster University | Coombes B.K.,Michael G Degroote Institute For Infectious Disease Research | Coombes B.K.,Farncombe Family Digestive Health Research Institute
Frontiers in Immunology | Year: 2015

Crohn's disease (CD) is an immune-mediated intestinal illness that significantly compromises health in many developed countries. Although definitive causes remain elusive, the required contribution of microbes in the progression of disease has become an accepted concept. Known CD risk factors, such as antibiotic use and acute infectious gastroenteritis, may impact the gut. This concept is now being explored with a view toward understanding the beneficial and unfavorable microbes that may be altered in numbers during such external insults. A comprehensive understanding of the microbial component to CD could be useful clinically as future therapies may focus on preventing risk exposures on susceptible individuals, eliminating harmful microbes, or restoring a protective gut microbiome. Here, we examine how acute infectious gastroenteritis and antibiotic exposure may impact the gut microbiota in the context of inflammation in CD. © 2015 Oberc and Coombes. Source

Popovski Z.,Hamilton Health Sciences | Popovski Z.,London Health Sciences Center | Mercuri M.,Columbia University | Mercuri M.,McMaster University | And 13 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2014

Objectives: Implementing evidence-based practice guidelines is challenging. We used a multifaceted, continuous educational approach to disseminate an up-to-date internal guideline adapted from published guidelines for management of intra-abdominal infections (IAI). Patients and methods: The intervention consisted of continuing educational sessions, internal guideline pocket cards and posters with collaboration among all key stakeholders starting in December 2010.We emphasized risk stratification and the use of ceftriaxone/metronidazole for treatment of low-risk IAI, and discouraged the use of fluoroquinolones due to the high local resistance rates.We then compared patients with IAI before the intervention (April-November 2010) to those after implementation of the guideline (April-November 2011) in a surgical unit at a tertiary care teaching hospital in Hamilton, Ontario, Canada. Antibiotic use was measured in in-hospital days of antibiotic therapy (DOT) per 1000 patient days (PD). Results: 152 and 145 patients with IAI were included in the pre-and post-intervention periods, respectively. There was a significant reduction in the proportion of patients who received ciprofloxacin therapy from 74% to 34% (OR 0.18, 95% CI 0.11-0.31) and in DOT/1000 PD from 221 to 74 (OR 0.3, 95% CI 0.2-0.3). Also, a reduction in the DOT/1000 PD for piperacillin/tazobactam was seen (from 116 to 67; OR 0.6, 95% CI 0.5-0.7). There was an increase in the use of ceftriaxone from 1.3% to 53% of patients (OR 85, 95% CI 20-515) and from 6 to 92 DOT/1000 PD (OR 17, 95% CI 10-25). This change in practice was sustained over >2 years since the end of the active intervention, as shown in the unit-wide antimicrobial utilization data. Conclusions: A multifaceted intervention aimed at all key stakeholders resulted in a high adherence to evidencebased treatment guidelines for IAI and has initiated a sustained culture change in prescribing of antibiotics. © The Author 2014. Source

Yao X.-D.,Michael G Degroote Institute For Infectious Disease Research | Omange R.W.,University of Manitoba | Henrick B.M.,Michael G Degroote Institute For Infectious Disease Research | Lester R.T.,University of British Columbia | And 4 more authors.
Mucosal Immunology | Year: 2014

Cohort studies of female commercial sex workers (CSWs) in Kenya were among the first to identify highly HIV-1-exposed seronegative (HESN) individuals. As natural resistance is usually mediated by innate immune mechanisms, we focused on determining whether expression and function of innate signaling pathways were altered locally in the genital mucosa of HESN CSWs. Our results demonstrated that selected pattern-recognition receptors (PRRs) were significantly reduced in expression in cervical mononuclear cells (CMCs) from HESN compared with the new HIV-negative (HIV-N) and HIV-positive (HIV-P) groups. Although baseline levels of secreted cytokines were reduced in CMCs of HESN, they were highly stimulated following exposure to ssRNA40 in vitro. Importantly, cervical epithelial cells from HESN also expressed reduced levels of PRRs, but Toll-like receptor 3 (TLR3) and TLR7 as well as nuclear factor-κB and activator protein 1 were highly expressed and activated. Lastly, inflammatory cytokines interleukin (IL)-1β, IL-8, and RANTES (regulated and normal T cell expressed and secreted) were detected at lower levels in cervicovaginal lavage of HESN compared with the HIV-N and HIV-P groups. Overall, our study reveals a local microenvironment of HIV resistance in the genital mucosa consisting of a finely controlled balance of basal immune quiescence with a focused and potent innate anti-viral response critical to resistance to sexual transmission of HIV-1. © 2014 Society for Mucosal Immunology. Source

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