Gene Polymorphisms Predisposing to Infectious Diarrhea

描述（由申请方提供）：暴露于肠道病原体后，感染性腹泻的表现是可变的，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，并且可以被分类为介导易感性的那些（即，宿主遗传因素，病原体受体），和损伤（即，液体和电解质通道的刺激、促炎细胞因子）。感染的消退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，遗传多态性，导致定性或定量的差异，这些介质中的一个或几个是部分负责发展感染和疾病后，暴露于肠道病原体。为此，我们将研究两个特征良好的感染性腹泻受试者群体。第一个研究小组将由来自发达国家的健康成年人组成，他们将前往腹泻细菌感染的风险地区。第二个研究组将由在德克萨斯大学休斯顿临床研究中心实验暴露于隐孢子虫的健康成年人组成。对于这两种情况，我们建议研究宿主基因的单核苷酸多态性（SNP），这些基因编码的蛋白质与易感性、疾病表现（损伤）的调节、根除（控制）和感染后的愈合相关。我们将重点关注三种具有不同病理生理学的潜在生物恐怖主义分子：肠毒素E。大肠杆菌引起的分泌性腹泻，肠聚集性E.大肠杆菌，一种引起炎症性腹泻的病原体，隐孢子虫是一种细胞内病原体。SNP将与肠道病原体的分离和临床疾病相关。SNPs的影响将在不同种族背景的背景下进行研究。感染的结果，因为它们涉及到主机的遗传因素的理解将用于设计生物防御干预措施，旨在改善风险评估。确定对肠道病原体的影响更敏感或更脆弱的人群，对于设计减少这些病原体可能导致疾病的影响的策略以及确定最有可能从预防、治疗和/或疫苗中受益的人群将是重要的。

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.