scholarly journals Role of Leptin-Mediated Colonic Inflammation in Defense against Clostridium difficile Colitis

2013 ◽  
Vol 82 (1) ◽  
pp. 341-349 ◽  
Author(s):  
Rajat Madan ◽  
Xiaoti Guo ◽  
Caitlin Naylor ◽  
Erica L. Buonomo ◽  
Donald Mackay ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Murine Model ◽  
Leptin Receptor ◽  
Mucosal Immune Response ◽  
Infectious Colitis ◽  
Content Type ◽  
Bacterial Peritonitis ◽  
Stat3 Signaling ◽  
Increased Risk

ABSTRACTThe role of leptin in the mucosal immune response toClostridium difficilecolitis, a leading cause of nosocomial infection, was studied in humans and in a murine model. Previously, a mutation in the receptor for leptin (LEPR) was shown to be associated with susceptibility to infectious colitis and liver abscess due toEntamoeba histolyticaas well as to bacterial peritonitis. Here we discovered that European Americans homozygous for the sameLEPRQ223R mutation (rs1137101), known to result in decreased STAT3 signaling, were at increased risk ofC. difficileinfection (odds ratio, 3.03;P= 0.015). The mechanism of increased susceptibility was studied in a murine model. Mice lacking a functional leptin receptor (db/db) had decreased clearance ofC. difficilefrom the gut lumen and diminished inflammation. Mutation of tyrosine 1138 in the intracellular domain of LepRb that mediates signaling through the STAT3/SOCS3 pathway also resulted in decreased mucosal chemokine and cell recruitment. Collectively, these data support a protective mucosal immune function for leptin inC. difficilecolitis partially mediated by a leptin-STAT3 inflammatory pathway that is defective in theLEPRQ223R mutation. Identification of the role of leptin in protection fromC. difficileoffers the potential for host-directed therapy and demonstrates a connection between metabolism and immunity.

scholarly journals Fecal Microbiota Transplantation Eliminates Clostridium difficile in a Murine Model of Relapsing Disease

2015 ◽  
Vol 83 (10) ◽  
pp. 3838-3846 ◽  
Author(s):  
Anna M. Seekatz ◽  
Casey M. Theriot ◽  
Caitlyn T. Molloy ◽  
Katherine L. Wozniak ◽  
Ingrid L. Bergin ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Gut Microbiota ◽  
Murine Model ◽  
Fecal Microbiota Transplantation ◽  
Clinical Signs ◽  
Fecal Microbiota ◽  
Content Type ◽  
Health Care Associated Infections ◽  
Specific Community

RecurrentClostridium difficileinfection (CDI) is of particular concern among health care-associated infections. The role of the microbiota in disease recovery is apparent given the success of fecal microbiota transplantation (FMT) for recurrent CDI. Here, we present a murine model of CDI relapse to further define the microbiota recovery following FMT. Cefoperazone-treated mice were infected withC. difficile630 spores and treated with vancomycin after development of clinical disease. Vancomycin treatment suppressed bothC. difficilecolonization and cytotoxin titers. However,C. difficilecounts increased within 7 days of completing treatment, accompanied by relapse of clinical signs. The administration of FMT immediately after vancomycin clearedC. difficileand decreased cytotoxicity within 1 week. The effects of FMT on the gut microbiota community were detectable in recipients 1-day posttransplant. Conversely, mice not treated with FMT remained persistently colonized with high levels ofC. difficile, and the gut microbiota in these mice persisted at low diversity. These results suggest that full recovery of colonization resistance againstC. difficilerequires the restoration of a specific community structure.

scholarly journals TheClostridium difficile spo0AGene Is a Persistence and Transmission Factor

2012 ◽  
Vol 80 (8) ◽  
pp. 2704-2711 ◽  
Author(s):  
Laura J. Deakin ◽  
Simon Clare ◽  
Robert P. Fagan ◽  
Lisa F. Dawson ◽  
Derek J. Pickard ◽  
...  
Keyword(s):  
Health Care ◽  
Clostridium Difficile ◽  
Murine Model ◽  
Persistent Infection ◽  
Transcriptional Regulator ◽  
Transmission Factor ◽  
Content Type ◽  
Antibiotic Associated Diarrhea ◽  
Significant Health

ABSTRACTClostridium difficileis a major cause of chronic antibiotic-associated diarrhea and a significant health care-associated pathogen that forms highly resistant and infectious spores. Spo0A is a highly conserved transcriptional regulator that plays a key role in initiating sporulation inBacillusandClostridiumspecies. Here, we use a murine model to study the role of theC. difficile spo0Agene during infection and transmission. We demonstrate thatC. difficile spo0Amutant derivatives can cause intestinal disease but are unable to persist within and effectively transmit between mice. Thus, theC. difficileSpo0A protein plays a key role in persistent infection, including recurrence and host-to-host transmission in mice.

scholarly journals Vulnerable adults in police custody

2019 ◽  
Vol 22 (1) ◽  
pp. 5-8
Author(s):  
Ian Cummins
Keyword(s):  
Design Methodology ◽  
Research Literature ◽  
Police Custody ◽  
England And Wales ◽  
Content Type ◽  
Increased Risk ◽  
Vulnerable Adults

Purpose The purpose of this paper is to discuss the recent National Appropriate Adult Network (NAAN) report on the role of the appropriate adult. Design/methodology/approach This paper is based on the NAAN report and a review of relevant policy and research literature. Findings There to Help 2 highlights that there are still significant gaps in the provision of appropriate adult schemes across England and Wales. These gaps potentially place vulnerable adults at increased risk. Originality/value This paper is a review of recent research.

scholarly journals Cyclic Diguanylate Regulates Virulence Factor Genes via Multiple Riboswitches inClostridium difficile

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Robert W. McKee ◽  
Carissa K. Harvest ◽  
Rita Tamayo
Keyword(s):  
Gene Expression ◽  
Clostridium Difficile ◽  
Biofilm Formation ◽  
Toxin Production ◽  
Intestinal Colonization ◽  
Cyclic Diguanylate ◽  
Signaling Molecule ◽  
Content Type ◽  
Surface Motility

ABSTRACTThe intracellular signaling molecule cyclic diguanylate (c-di-GMP) regulates many processes in bacteria, with a central role in controlling the switch between motile and nonmotile lifestyles. Recent work has shown that inClostridium difficile(also calledClostridioides difficile), c-di-GMP regulates swimming and surface motility, biofilm formation, toxin production, and intestinal colonization. In this study, we determined the transcriptional regulon of c-di-GMP inC. difficile,employing overexpression of a diguanylate cyclase gene to artificially manipulate intracellular c-di-GMP. Consistent with prior work, c-di-GMP regulated the expression of genes involved in swimming and surface motility. c-di-GMP also affected the expression of multiple genes encoding cell envelope proteins, several of which affected biofilm formationin vitro. A substantial proportion of the c-di-GMP regulon appears to be controlled either directly or indirectly via riboswitches. We confirmed the functionality of 11 c-di-GMP riboswitches, demonstrating their effects on downstream gene expression independent of the upstream promoters. The class I riboswitches uniformly functioned as “off” switches in response to c-di-GMP, while class II riboswitches acted as “on” switches. Transcriptional analyses of genes 3′ of c-di-GMP riboswitches over a broad range of c-di-GMP levels showed that relatively modest changes in c-di-GMP levels are capable of altering gene transcription, with concomitant effects on microbial behavior. This work expands the known c-di-GMP signaling network inC. difficileand emphasizes the role of the riboswitches in controlling known and putative virulence factors inC. difficile.IMPORTANCEInClostridium difficile, the signaling molecule c-di-GMP regulates multiple processes affecting its ability to cause disease, including swimming and surface motility, biofilm formation, toxin production, and intestinal colonization. In this study, we used RNA-seq to define the transcriptional regulon of c-di-GMP inC. difficile. Many new targets of c-di-GMP regulation were identified, including multiple putative colonization factors. Transcriptional analyses revealed a prominent role for riboswitches in c-di-GMP signaling. Only a subset of the 16 previously predicted c-di-GMP riboswitches were functionalin vivoand displayed potential variability in their response kinetics to c-di-GMP. This work underscores the importance of studying c-di-GMP riboswitches in a relevant biological context and highlights the role of the riboswitches in controlling gene expression inC. difficile.

scholarly journals Germinant Synergy FacilitatesClostridium difficileSpore Germination under Physiological Conditions

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Travis J. Kochan ◽  
Michelle S. Shoshiev ◽  
Jessica L. Hastie ◽  
Madeline J. Somers ◽  
Yael M. Plotnick ◽  
...  
Keyword(s):  
Amino Acids ◽  
Clostridium Difficile ◽  
Spore Germination ◽  
Bile Salts ◽  
Gi Tract ◽  
Infectious Diarrhea ◽  
Content Type ◽  
Increased Risk ◽  
Calcium Reabsorption

ABSTRACTClostridium difficileis a Gram-positive obligate anaerobe that forms spores in order to survive for long periods in the unfavorable environment outside a host.C. difficileis the leading cause of nosocomial infectious diarrhea worldwide.C. difficileinfection (CDI) arises after a patient treated with broad-spectrum antibiotics ingests infectious spores. The first step inC. difficilepathogenesis is the metabolic reactivation of dormant spores within the gastrointestinal (GI) tract through a process known as germination. In this work, we aim to elucidate the specific conditions and the location within the GI tract that facilitate this process. Our data suggest thatC. difficilegermination occurs through a two-step biochemical process that is regulated by pH and bile salts, amino acids, and calcium present within the GI tract. Maximal germination occurs at a pH ranging from 6.5 to 8.5 in the terminal small intestine prior to bile salt and calcium reabsorption by the host. Germination can be initiated by lower concentrations of germinants when spores are incubated with a combination of bile salts, calcium, and amino acids, and this synergy is dependent on the availability of calcium. The synergy described here allows germination to proceed in the presence of inhibitory bile salts and at physiological concentrations of germinants, effectively decreasing the concentrations of nutrients required to initiate an essential step of pathogenesis.IMPORTANCEClostridium difficileis an anaerobic spore-forming human pathogen that is the leading cause of nosocomial infectious diarrhea worldwide. Germination of infectious spores is the first step in the development of aC. difficileinfection (CDI) after ingestion and passage through the stomach. This study investigates the specific conditions that facilitateC. difficilespore germination, including the following: location within the gastrointestinal (GI) tract, pH, temperature, and germinant concentration. The germinants that have been identified in culture include combinations of bile salts and amino acids or bile salts and calcium, butin vitro, these function at concentrations that far exceed normal physiological ranges normally found in the mammalian GI tract. In this work, we describe and quantify a previously unreported synergy observed when bile salts, calcium, and amino acids are added together. These germinant cocktails improve germination efficiency by decreasing the required concentrations of germinants to physiologically relevant levels. Combinations of multiple germinant types are also able to overcome the effects of inhibitory bile salts. In addition, we propose that the acidic conditions within the GI tract regulateC. difficilespore germination and could provide a biological explanation for why patients taking proton pump inhibitors are associated with increased risk of developing a CDI.

Property investment: gearing and the equity rate of return

2019 ◽  
Vol 37 (3) ◽  
pp. 323-328 ◽  
Author(s):  
Nick French
Keyword(s):  
Design Methodology ◽  
Investment Project ◽  
Equity Returns ◽  
Rate Of Return ◽  
Content Type ◽  
Bank Rate ◽  
Increased Risk ◽  
Practical Implications ◽  
Different Levels

Purpose The purpose of this paper is to comment upon the relatively straightforward but often misunderstood role of gearing (or leverage) on the potential equity return of a property investment. Design/methodology/approach This education briefing is an explanation of the upside and downside risk of borrowing (at different levels) to successful investment. Findings The use of gearing can greatly enhance equity returns but at an increased risk. Practical implications The process of borrowing at a bank rate below the return rate on an investment project can increase the equity return of the project as long as all incomes and discount rate remain at appropriate levels. Originality/value This is a review of existing models.

scholarly journals Observations on the Role of TcdE Isoforms in Clostridium difficile Toxin Secretion

2015 ◽  
Vol 197 (15) ◽  
pp. 2600-2609 ◽  
Author(s):  
Revathi Govind ◽  
Leah Fitzwater ◽  
Rebekah Nichols
Keyword(s):  
Amino Acids ◽  
Clostridium Difficile ◽  
Cell Viability ◽  
Virulence Factors ◽  
Start Codon ◽  
Nosocomial Pathogen ◽  
Content Type ◽  
Antibiotic Associated Diarrhea ◽  
Toxin Secretion

ABSTRACTClostridium difficileis a major nosocomial pathogen and the principal causative agent of antibiotic-associated diarrhea. The toxigenicC. difficilestrains that cause disease secrete virulence factors, toxin A and toxin B, that cause colonic injury and inflammation.C. difficiletoxins have no export signature and are secreted by an unusual mechanism that involves TcdE, a holin-like protein. We isolated a TcdE mutant of the epidemic R20291 strain with impaired toxin secretion, which was restored by complementation with functional TcdE. In the TcdE open reading frame (ORF), we identified three possible translation start sites; each translated isoform may play a specific role in TcdE-controlled toxin release. We created plasmid constructs that express only one of the three TcdE isoforms and complemented the TcdE mutant with these isoforms. Western blot analysis of the complemented strains demonstrated that TcdE is translated efficiently from the start codon at the 25th and 27th positions in the predicted ORF, producing proteins with 142 amino acids (TcdE142) and 140 amino acids (TcdE140), respectively. TcdE166was not detected when expressed from its own ribosomal binding site (RBS). The effects of all three TcdE isoforms onC. difficilecell viability and toxin release were determined. Among the three isoforms, overexpression of TcdE166and TcdE142had a profound effect on cell viability compared to the TcdE140isoform. Similarly, TcdE166and TcdE142facilitated toxin release more efficiently than did TcdE140. The importance of these variations among TcdE isoforms and their role in toxin release are discussed.IMPORTANCEC. difficileis a nosocomial pathogen that has become the most prevalent cause of antibiotic-associated diarrhea in North America and in several countries in Europe. Most strains ofC. difficileproduce two high-molecular-weight toxins that are regarded as the primary virulence factors. The mechanism by which these large toxins are secreted from bacterial cells is not yet clear but involves TcdE, a holin-like protein. In this work, we show that TcdE could be translated from three different start codons, resulting in the production of three TcdE isoforms. Furthermore, we investigated the role of these isoforms in toxin release and cell lysis inC. difficile. An understanding of TcdE-dependent toxin secretion may be helpful for the development of strategies for preventing and treatingC. difficileinfections.

scholarly journals Physiologic Expression of the Candida albicans Pescadillo Homolog Is Required for Virulence in a Murine Model of Hematogenously Disseminated Candidiasis

2012 ◽  
Vol 11 (12) ◽  
pp. 1552-1556 ◽  
Author(s):  
Priya Uppuluri ◽  
Ashok K. Chaturvedi ◽  
Niketa Jani ◽  
Read Pukkila-Worley ◽  
Carlos Monteagudo ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Murine Model ◽  
Critical Role ◽  
Growth Defect ◽  
Mammalian Host ◽  
Developmental Cycle ◽  
Yeast Growth ◽  
Content Type ◽  
Disseminated Candidiasis

ABSTRACT Morphogenetic conversions contribute to the pathogenesis of Candida albicans invasive infections. Many studies to date have convincingly demonstrated a link between filamentation and virulence; however, relatively little is known regarding the role of the filament-to-yeast transition during the pathogenesis of invasive candidiasis. We previously identified the C. albicans pescadillo homolog ( PES1 ) as essential during yeast growth and growth of lateral yeast on hyphae but not during hyphal growth. Furthermore, we demonstrated that PES1 is required for virulence in vivo in a Galleria mellonella larva model of candidiasis. Here, we have used a regulatable tetO-PES1 / pes1 strain to assess the contribution of C. albicans PES1 to pathogenesis in the commonly used and clinically relevant murine model of hematogenously disseminated candidiasis. Our results indicate that a physiologically controlled level of PES1 expression is required for full virulence in this animal model, with virulence defects observed both when PES1 is overexpressed and and when it is depleted. The pathogenetic defect of cells depleted of PES1 is not due to a general growth defect, as demonstrated by the fact that PES1 -depleted cells still kill Caenorhabditis elegans as efficiently as the wild type due to hyphal outgrowth through worm tissues. Our results suggest a critical role of lateral yeast growth in the ability of C. albicans to normally proliferate within tissues, as well as a pivotal role for Pes1 in the normal developmental cycle of C. albicans within the mammalian host during infection.

scholarly journals Clostridium difficile PCR Ribotype 018, a Successful Epidemic Genotype

2015 ◽  
Vol 53 (8) ◽  
pp. 2575-2580 ◽  
Author(s):  
Rossella Baldan ◽  
Alberto Trovato ◽  
Valentina Bianchini ◽  
Anna Biancardi ◽  
Paola Cichero ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Genetic Relatedness ◽  
Public Health Problem ◽  
Antibiotic Consumption ◽  
Transmission Capacity ◽  
Predominant Genotype ◽  
Content Type ◽  
Molecular Features ◽  
Severity Of The Disease

Clostridium difficileinfection (CDI) became a public health problem for the global spreading of the so-called hypervirulent PCR ribotypes (RTs) 027 and 078, associated with increases in the transmission and severity of the disease. However, especially in Europe, several RTs are prevalent, and the concept of hypervirulence is currently debated. We investigated the toxin and resistance profiles and the genetic relatedness of 312C. difficilestrains isolated in a large Italian teaching hospital during a 5-year period. We evaluated the role of CDI-related antibiotic consumption and infection control practices on the RT predominance in association with their molecular features and transmission capacity. Excluding secondary cases due to nosocomial transmission, RT018 was the predominant genotype (42.4%) followed by RT078 (13.6%), while RT027 accounted for 0.8% of the strains. RT078 was most frequently isolated from patients in intensive care units. Its prevalence significantly increased over time, but its transmission capacity was very low. In contrast, RT018 was highly transmissible and accounted for 95.7% of the secondary cases. Patients with the RT018 genotype were significantly older than those with RT078 and other RTs, indicating an association between epidemic RT and age. We provide here the first epidemiological evidence to consider RT018 as a successful epidemic genotype that deserves more attention in clinical practice.

scholarly journals Kibdelomycin Is a Potent and Selective Agent against Toxigenic Clostridium difficile

2014 ◽  
Vol 58 (4) ◽  
pp. 2387-2392 ◽  
Author(s):  
Lynn Miesel ◽  
David W. Hecht ◽  
James R. Osmolski ◽  
Dale Gerding ◽  
Amy Flattery ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Oral Dose ◽  
Gram Positive ◽  
Hamster Model ◽  
Content Type ◽  
Daily Oral Dose ◽  
Log Reduction ◽  
Increased Risk ◽  
Lethal Infection ◽  
Gram Negative Organisms

ABSTRACTClostridium difficileis the causative agent ofC. difficile-associated diarrhea (CDAD), with increased risk in elderly populations. Kibdelomycin, a novel natural-product inhibitor of type II topoisomerase enzymes, was evaluated for activity againstC. difficileand gastrointestinal anaerobic organisms. ToxigenicC. difficileisolates (n= 168) from U.S. hospitals and anaerobic Gram-positive and Gram-negative organisms (n= 598) from Chicago-area hospitals were tested. Kibdelomycin showed potent activity against toxigenicC. difficile(MIC90= 0.25 μg/ml) and most Gram-positive aerobic organisms but had little activity againstBacteroidesspecies (MIC50> 32 μg/ml;n= 270). Potent anti-C. difficileactivity was also observed in the hamster model ofC. difficilecolitis. Dosing at 1.6 mg/kg (twice-daily oral dose) resulted in protection from a lethal infection and a 2-log reduction inC. difficilececal counts. A 6.25-mg/kg twice-daily oral dose completely eliminated detectableC. difficilecounts in cecal contents. A single 6.25-mg/kg oral dose showed that cecal contents were exposed to the drug at >2 μM (eightfold higher than the MIC), with no significant plasma exposure. These findings support further exploration of kibdelomycin for development of an anti-C. difficileagent.

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