Gene Polymorphisms Predisposing to Infectious Diarrhea

描述(申请人提供)：接触肠道病原体后，感染性腹泻的表现多种多样，取决于宿主和病原体因素。多种宿主因素调节感染的可能性或症状的严重程度，可归类为介导易感性(即宿主遗传因素、病原体受体)和损伤(即对液体和电解质通道的刺激、促炎细胞因子)的因素。感染的解决取决于有助于控制和愈合阶段的因素(即抗炎细胞因子和特异性免疫)。我们的中心假设是，导致其中一个或几个介质质量或数量差异的基因多态是接触肠道病原体后感染和疾病发展的部分原因。为此，我们将研究两个具有良好特征的感染性腹泻受试者群体。第一个研究小组将由健康的成年人组成，他们从发达国家前往易感染腹泻细菌的地区。第二个研究小组将由在德克萨斯大学休斯顿临床研究中心实验接触隐孢子虫的健康成年人组成。对于这两种疾病，我们建议研究编码蛋白的宿主单核苷酸多态(SNPs)，这些蛋白与易感性、疾病表现的调节(损伤)、根除(控制)和感染后的愈合相关。我们将集中讨论三种具有潜在生物恐怖主义用途的病原体：引起分泌性腹泻的产肠毒素大肠埃希氏菌、引起炎症性腹泻的肠聚集性大肠埃希氏菌和细胞内病原体隐孢子虫。SNPs将与肠道病原体的分离和临床疾病相关。将在不同种族背景的背景下审查SNPs的影响。了解感染后果与宿主遗传因素的关系，将有助于设计旨在改进风险评估的生物防御干预措施。确定更易受肠道病原体影响或更易受肠道病原体影响的人群，对于制定减少这些病原体在致病和确定最有可能从预防、治疗和(或)疫苗中受益的人群的影响的战略具有重要意义。

DESCRIPTION (provided by applicant): After exposure to an enteropathogen, the manifestations of infectious diarrhea are variable and depend on host and pathogen factors. A variety of host factors modulate the likelihood of infection or severity of symptoms and can be categorized as those that mediate susceptibility (i.e., host genetic factors, pathogen receptors), and injury (i.e., stimulation of fluid and electrolyte channels, pro inflammatory cytokines). Resolution of infection is determined by factors that contribute to the phases of control and healing (i.e., anti-inflammatory cytokines and specific immunity). Our central hypothesis is that genetic polymorphisms that lead to qualitative or quantitative differences in one or several of these mediators are partially responsible for the development of infection and illness after exposure to enteric pathogens. To this end we will study two well-characterized populations of subjects with infectious diarrhea. The first study group will consist of healthy adults traveling from developed nations to areas of risk for infection with bacterial agents of diarrhea. The second study group will consist of healthy adults experimentally exposed to Cryptosporidium at the University of Texas - Houston Clinical Research Center. For both we propose to investigate host single nucleotide polymorphisms (SNPs) of genes that encode proteins that are associated with either susceptibility, modulation of disease manifestation (injury), eradication (control) and healing after infection. We will focus on three agents with potential for bioterrorism use by waterborne or food borne routes with distinct pathophysiology; enterotoxigenic E. coli a cause of secretory diarrhea, Enteroaggregative E. coli, a cause of inflammatory diarrhea and Cryptosporidium an intracellular pathogen. SNPs will be correlated with the isolation of an enteropathogen and clinical illness. The impact of SNPs will be examined in the context of different ethnic backgrounds. The understanding of the outcome of infection as they relate to host genetic factors will be of use in designing biodefense interventions that are directed towards improving risk assessment. The identification of populations that are more susceptible or vulnerable to the effects of enteric pathogens will be important in the design of strategies to decrease the impact that these agents may have in causing disease and defining the populations most likely to benefit from prevention, treatment and or vaccines.