Shiga Toxin Encoding Phage and Intestinal E.coli

性状（由申请方提供）：产滋贺毒素大肠埃希菌，包括O 157：H7，是重要的新兴病原体。 细菌定植与肠道紊乱有关;然而，严重的、潜在致命的出血性腹泻（出血性结肠炎）症状和导致溶血性尿毒综合征（HUS）的肾脏破坏是由于细菌毒素滋贺毒素所致。 滋贺毒素的基因由温和噬菌体在晚期基因操纵子中编码。当噬菌体裂解循环被诱导时，滋贺毒素与产生病毒颗粒和细菌裂解所必需的基因一起沿着表达。 噬菌体介导的细菌裂解是毒素分泌所必需的。 致病性O 157：H7感染过程中产生的病毒颗粒可感染非致病性肠道E.杆菌 当这种情况发生时，以前无害的E。大肠杆菌会产生滋贺毒素并放大致病过程。 我们的初步数据表明，肠道植物群产生的滋贺毒素可能是大量的，严重的，可能危及生命的疾病更有可能发生在个人的肠道植物群可以感染的滋贺毒素噬菌体。 相反，具有对滋贺毒素噬菌体具有抗性的肠道植物群的个体将免受严重疾病的影响。 目前，通过E.大肠杆菌O 157：H7，因为感染剂量非常低，抗生素治疗非但无益，反而会加速致命疾病的进展。 我们建议开发将肠道植物群转化为噬菌体抗性的方法，作为控制由产生滋贺毒素的病原体引起的疾病的治疗方法。 这一点尤其重要，因为一旦疾病发展，除了支持性护理之外，没有任何治疗。本申请的具体目的是：1）表征在存在敏感或抗性人肠E.大肠杆菌;和2）开发使用小鼠疾病模型将肠植物群转化为噬菌体抗性的方法。

DESCRIPTION (provided by applicant): Shiga toxin-producing Escherichia coli, including O157:H7, are emerging pathogens of major importance. Bacterial colonization is associated with intestinal disturbances; however, the severe, potentially fatal symptoms of bloody diarrhea (hemorrhagic colitis) and destruction of the kidney leading to hemolytic uremic syndrome (HUS) are due to a bacterial toxin, Shiga toxin. The genes for Shiga toxin are encoded by a temperate bacteriophage in the late gene operon. Shiga toxin is expressed when the phage lytic cycle is induced, along with the genes necessary for production of viral particles and bacterial lysis. Phage-mediated bacterial lysis is necessary for toxin secretion. The viral particles produced during infection with the pathogenic O157:H7 can infect the nonpathogenic intestinal E. coli. When this occurs, the previously harmless E. coli will produce Shiga toxin and amplify the pathogenic process. Our preliminary data suggest that the Shiga toxin production by intestinal flora can be substantial and that severe, possibly life-threatening disease is more likely to occur in individuals whose intestinal flora can be infected by the Shiga toxin phage. In contrast, individuals with intestinal flora that are resistant to the Shiga toxin phage will be protected from severe disease. Currently, it is difficult to prevent disease by E. coli O157:H7 since the infectious dose is very low, and antibiotic treatment, instead of being beneficial, can enhance progression to fatal disease. We propose to develop methods to convert the intestinal flora to phage-resistance as a therapeutic approach to controlling disease caused by Shiga toxin-producing pathogens. This is especially important since there is no treatment, other than supportive care, once disease has developed. The specific aims of this application are to: 1) Characterize Shiga toxin production by clinical isolates of O157:H7 in the presence of susceptible or resistant human intestinal E. coli; and 2) Develop methods to convert intestinal flora to phage resistance using a mouse model of disease.