Clinical Significance of Clostridium difficile Toxin Variants
艰难梭菌毒素变异体的临床意义
基本信息
- 批准号:7686663
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-04-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:1 year oldADP Ribose TransferasesActinsAffectAgeAnimal ModelAntibioticsBiological AssayCanadaCessation of lifeCharacteristicsClinicalClostridium difficileColitisCytotoxinDataDiagnosisDiarrheaDiseaseDisease OutbreaksElderlyEpidemicEpithelialEuropeFrequenciesGene ExpressionGenesGenomeGrant ReviewHamstersHealthcareHospital RecordsHospitalsHumanIn VitroIntestinesLaboratoriesLeadLength of StayLightLinkLiquid substanceModelingMolecularMusNorth AmericaOryctolagus cuniculusPathogenesisPathogenicityPatientsPersonsPhasePrincipal InvestigatorProductionQuebecReportingResearchRestriction fragment length polymorphismRiskRisk FactorsSeverity of illnessTestingTight JunctionsToxinToxoidsVaccinationVariantVeteransVeterans HospitalsVirulenceVirulence FactorsVirulentWorkabstractingclinically significantfactor Cfluoroquinolone resistanceimprovedin vitro testingmonolayermutantpatient populationpolarized cellprogramspublic health relevanceresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant):
PROJECT SUMMARY/ABSTRACT Clostridium difficile-associated disease (CDAD) is an increasing problem in Veterans Hospitals and other hospitals throughout North America. Recent multi-hospital outbreaks in Canada and in the U.S. have been linked to the emergence of a specific C. difficile toxin variant, referred to as BI/NAP1/027 which may explain, at least in part, the overall increase in national rates of CDAD. The toxin variant BI/NAP1/027 strains are characterized by increased production of toxin A and B (the major known virulence factors of C. difficile), the presence of an additional toxin, referred to as binary toxin CDT, as well as increased resistance to fluoroquinolone antibiotics. Because of their association with more severe disease in these hospital outbreaks, the BI/NAP1/027 strains have been referred to as hypervirulent. Determining the contribution of the various toxins and other factors to hypervirulence of the BI strains will not only improve the understanding of why these strains have become the dominant epidemic strains in North America, but will also help elucidate the fundamental molecular steps in the pathogenesis of CDAD. Historically, toxin A has been implicated as the primary virulence determinant of C. difficile because of its potent enterotoxic activity and the ability of toxin A alone to produce disease in animal models. However, clinical observations on the naturally-occurring toxin A- negative, B-positive (A-/B+) variant strains, and our work demonstrating virulence of A-/B+ strains in the hamster model, in addition to other recent evidence, suggest that toxin B, not A, is the essential virulence factor in C. difficile. We hypothesize that toxin B, not toxin A is the essential virulence factor of C. difficile, including epidemic BI strains. We also hypothesize that the frequency of a particular strain in our hospital will be determined in part by the level of toxin B production by that strain. The specific objectives of this proposal are: Objective 1: To prospectively screen C. difficile clinical isolates to determine the frequency of specific strains, correlate toxin production in vitro with frequency, and to obtain candidate hypervirulent BI isolates for construction of mutants. Objective 2: To construct independent mutants of toxin B and toxin A in a hypervirulent BI strain. Objective 3: To conduct in vitro analysis of the BI-derived toxin B and toxin A mutants for toxin production and for pathogenicity locus (PaLoc) gene expression. Objective 4: To test the independent toxin B and toxin A mutants in the hamster model to determine if virulence is abrogated.
PUBLIC HEALTH RELEVANCE:
PROJECT NARRATIVE Potential impact on Veterans Health Care: CDAD remains the major cause of hospital-acquired infectious diarrhea and VA hospitals have been particularly affected because the risk factors for CDAD, advanced age, prolonged hospital stay and frequent antibiotic exposure are characteristics of VA Hospital patients. An improved understanding of the pathogenesis of CDAD, should lead to new treatments, diagnosis, and strategies to interrupt the ongoing epidemic of CDAD affecting VA and non-VA hospitalized patients.
描述(由申请人提供):
项目摘要/摘要艰难梭菌相关性疾病(CDAD)在整个北美的退伍军人医院和其他医院是一个日益严重的问题。最近在加拿大和美国多家医院爆发的疫情与一种特殊的艰难梭菌毒素变种BI/NAP1/027的出现有关,这可能至少在一定程度上解释了全国CDAD发病率的总体上升。毒素变异株BI/NAP1/027的特征是毒素A和B(艰难梭菌的主要毒力因子)的产生增加,存在一种额外的毒素,称为二元毒素CDT,以及对氟喹诺酮类抗生素的耐药性增加。由于它们与这些医院暴发的更严重的疾病有关,BI/NAP1/027菌株被称为超强毒力。确定各种毒素和其他因素对BI毒株超强毒力的贡献,不仅有助于理解这些毒株成为北美主要流行毒株的原因,而且有助于阐明CDAD发病的基本分子步骤。从历史上看,A毒素一直被认为是艰难梭菌的主要毒力决定因素,因为它具有很强的肠毒素活性,而且A毒素本身能够在动物模型中引起疾病。然而,对自然产生的毒素A-阴性、B-阳性(A-/B+)变异株的临床观察,以及我们在仓鼠模型中证明A-/B+菌株的毒力的工作,以及其他最近的证据表明,艰难梭菌的基本毒力因子是毒素B,而不是A。我们推测艰难梭菌的基本毒力因子是毒素B,而不是毒素A,包括BI流行株。我们还假设,某一特定菌株在我们医院的出现频率将部分取决于该菌株产生B毒素的水平。本研究的具体目标是:目的1:前瞻性筛选艰难梭菌临床分离株,确定特定菌株的频率,将体外毒素产生与频率相关联,并获得可用于构建突变株的超强毒力BI候选菌株。目的:在超强毒力BI株中构建毒素B和毒素A的独立突变体。目的:对BI来源的毒素B和毒素A突变株进行体外毒素产生和致病基因(PaLoc)基因表达的分析。目的:在金黄地鼠模型中检测毒素B和毒素A的独立突变体,以确定其毒力是否被取消。
公共卫生相关性:
项目描述对退伍军人医疗保健的潜在影响:CDAD仍然是医院获得性感染性腹泻的主要原因,退伍军人医院受到的影响尤其大,因为CDAD的风险因素、高龄、住院时间延长和频繁接触抗生素是退伍军人医院患者的特点。对CDAD发病机制的更好理解,应该导致新的治疗、诊断和策略,以中断影响VA和非VA住院患者的CDAD的持续流行。
项目成果
期刊论文数量(0)
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Stuart Brian Johnson其他文献
Stuart Brian Johnson的其他文献
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{{ truncateString('Stuart Brian Johnson', 18)}}的其他基金
Impact of Binary Toxin on Recurrent Clostridium difficile Infection
二元毒素对复发性艰难梭菌感染的影响
- 批准号:
9045377 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Impact of Binary Toxin on Recurrent Clostridium difficile Infection
二元毒素对复发性艰难梭菌感染的影响
- 批准号:
9339553 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Clinical Significance of Clostridium difficile Toxin Variants
艰难梭菌毒素变异体的临床意义
- 批准号:
8262607 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Clinical Significance of Clostridium difficile Toxin Variants
艰难梭菌毒素变异体的临床意义
- 批准号:
8195597 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Clinical Significance of Clostridium difficile Toxin Variants
艰难梭菌毒素变异体的临床意义
- 批准号:
7783810 - 财政年份:2009
- 资助金额:
-- - 项目类别: