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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.


Allison S.E.,McMaster University | Allison S.E.,Michael G Degroote Institute For Infectious Disease Research | Silphaduang U.,McMaster University | Silphaduang U.,Public Health Agency of Canada | And 6 more authors.
Journal of Bacteriology | Year: 2012

Escherichia coli O157:H7 is a gastrointestinal pathogen that has become a serious public health concern, as it is associated with outbreaks and severe diseases such as hemolytic-uremic syndrome. The molecular basis of its greater virulence than that of other serotypes is not completely known. OI-1 is a putative fimbria-encoding genomic island that is found almost exclusively in O157:H7 Shiga toxin-producing E. coli strains and may be associated with the enhanced pathogenesis of these strains. In this study, we identified and characterized a novel repressor of flagellar synthesis encoded by OI-1. We showed that deletion of Z0021 increased the motility of E. coli O157:H7, which correlated with an increase in flagellin production and enhanced assembly of flagella on the cell surface. In contrast, overexpression of Z0021 inhibited motility. We demonstrated that Z0021 exerted its regulatory effects downstream of the transcription and translation of flhDC but prior to the activation of class II/III promoters. Furthermore, the master regulator of flagellar synthesis, FlhD4C2, was shown to be a high-copy suppressor of the nonmotile phenotype associated with elevated levels of Z0021-a finding consistent with Z0021-FlhD4C2 being a potential regulatory complex. This work provides insight into the mechanism by which Z0021, which we have named fmrA, represses flagellar synthesis and is the first report of a fimbrial-operon-encoded inhibitor of motility in E. coli O157:H7. © 2012, American Society for Microbiology.


Henrick B.M.,Michael G Degroote Institute For Infectious Disease Research | Yao X.-D.,Michael G Degroote Institute For Infectious Disease Research | Drannik A.G.,Michael G Degroote Institute For Infectious Disease Research | Abimiku A.,University of Maryland, Baltimore | Rosenthal K.L.,Michael G Degroote Institute For Infectious Disease Research
AIDS | Year: 2014

Objectives: We previously demonstrated that immunodepletion of soluble Toll-like receptor 2 (sTLR2) from human breast milk significantly increased HIV infection in vitro. The aims of this study were to characterize sTLR2 levels in breast milk from HIVinfected and uninfected women, and identify a mechanism by which sTLR2 inhibits HIV-induced cellular activation and infection. Design: Blinded studies of breast milk from HIV-infected and uninfected Nigerian and Canadian women were evaluated for levels of sTLR2, proinflammatory cytokines and viral antigenemia. In-vitro experiments were conducted using cell lines to assess sTLR2 function in innate responses and effect on HIV infection. Results: Breast milk from HIV-infected women showed significantly higher levels of sTLR2 than uninfected breast milk. Further, sTLR2 levels correlated with HIV-1 p24 and interleukin (IL)-15, thus suggesting a local innate compensatory response in the HIV-infected breast. Given the significantly higher levels of sTLR2 in breast milk from HIV-infected women, we next demonstrated that mammary epithelial cells and macrophages, which are prevalent in milk, produced significantly increased levels of sTLR2 following exposure to HIV-1 proteins p17, p24 and gp41 or the TLR2 ligand, Pam3CSK4. Our results also demonstrated that sTLR2 physically interacts with p17, p24 and gp41 and inhibits HIV-induced nuclear factor kappa-light-chain-enhancer of activated B cells activation, and inflammation. Importantly, binding of sTLR2 to HIV-1 proteins inhibited a TLR2-dependent increase in chemokine receptor 5 expression, thus resulting in significantly reduced HIV-1 infection. Conclusion: These results indicate novel mechanisms by which sTLR2 plays a critical role in inhibiting mother-to-child HIV transmission. © 2014 Wolters Kluwer Health.


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.


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.


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.


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.


Small C.L.,Michael G Degroote Institute For Infectious Disease Research | Small C.L.,Inflamax Research | Xing L.,Michael G Degroote Institute For Infectious Disease Research | McPhee J.B.,Michael G Degroote Institute For Infectious Disease Research | And 5 more authors.
PLoS Pathogens | Year: 2016

Crohn’s disease (CD) is a chronic inflammatory condition of diverse etiology. Exposure to foodborne pathogens causing acute gastroenteritis produces a long-term risk of CD well into the post-infectious period but the mechanistic basis for this ongoing relationship to disease onset is unknown. We developed two novel models to study the comorbidity of acute gastroenteritis caused by Salmonella Typhimurium or Citrobacter rodentium in mice colonized with adherent-invasive Escherichia coli (AIEC), a bacterial pathobiont linked to CD. Here, we show that disease activity in the post-infectious period after gastroenteritis is driven by the tissue-associated expansion of the resident AIEC pathobiont, with an attendant increase in immunopathology, barrier defects, and delays in mucosal restitution following pathogen clearance. These features required AIEC resistance to host defense peptides and a fulminant inflammatory response to the enteric pathogen. Our results suggest that individuals colonized by AIEC at the time of acute infectious gastroenteritis may be at greater risk for CD onset. Importantly, our data identify AIEC as a tractable disease modifier, a finding that could be exploited in the development of therapeutic interventions following infectious gastroenteritis in at-risk individuals. © 2016 Small et al.


PubMed | Michael G Degroote Institute For Infectious Disease Research
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2012

Expansion into new host niches requires bacterial pathogens to adapt to changes in nutrient availability and to evade an arsenal of host defenses. Horizontal acquisition of Salmonella Pathogenicity Island (SPI)-2 permitted the expansion of Salmonella enterica serovar Typhimurium into the intracellular environment of host cells by allowing it to deliver bacterial effector proteins across the phagosome membrane. This is facilitated by the SsrA-SsrB two-component regulatory system and a type III secretion system encoded within SPI-2. SPI-2 acquisition was followed by evolution of existing regulatory DNA, creating an expanded SsrB regulon involved in intracellular fitness and host infection. Here, we identified an SsrB-regulated operon comprising an ABC transporter in Salmonella. Biochemical and structural studies determined that the periplasmic solute-binding component, STM1633/DalS, transports D-alanine and that DalS is required for intracellular survival of the bacteria and for fitness in an animal host. This work exemplifies the role of nutrient exchange at the host-pathogen interface as a critical determinant of disease outcome.


Reid-Yu S.A.,Michael G Degroote Institute For Infectious Disease Research | Reid-Yu S.A.,McMaster University | Tuinema B.R.,Michael G Degroote Institute For Infectious Disease Research | Tuinema B.R.,McMaster University | And 7 more authors.
PLoS Pathogens | Year: 2015

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. © 2015 Reid-Yu et al.

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