Search For New and Emerging Etiologic Agents

寻找新的和正在出现的病原体

• 批准号: 7964222
• 负责人: Robert H. Purcell
• 金额: $ 78.89万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964222
• 关键词: Accounting; Acute; Animals; Antibodies; Biochemical; Biological; Blood donor; Cattle; Characteristics; Child; Chronic; Chronic Hepatitis; Cirrhosis; Clinical; Collaborations; Communicable Diseases; Communities; Developed Countries; Developing Countries; Diagnosis; Diagnostic; Disease; Disease Outbreaks; Domestic Animals; Egypt; Epidemiology; Etiology; Evaluation; Family suidae; Food Chain; Gastroenteritis; Gastrointestinal Diseases; Goals; Goat; Hepatic; Hepatitis; Hepatitis A; Hepatitis E; Hepatitis E virus; Hepatitis Viruses; High Prevalence; Human; Immune response; India; Infection; Laboratory Rat; Life; Liver; Liver diseases; Los Angeles; Malignant neoplasm of liver; Medical; Microarray Analysis; Minor; Molecular; Molecular Biology Techniques; Monitor; Mucocutaneous Lymph Node Syndrome; New Agents; Pakistan; Pan Genus; Patients; Phase; Predisposition; Process; Public Health; Rattus; Rattus norvegicus; Sampling; Saudi Arabia; Serial Passage; Seroepidemiologic Studies; Serological; Serum; Sheep; Source; Technology; Transfusion; United States; Virus; Virus Diseases; base; experience; follower of religion Jewish; man; response; transmission process

Acute or chronic non-A, B, C, D, E hepatitis is being studied for biological, serological or molecular evidence of transmissible agents. Fulminant non-A to E hepatitis remains a diagnostic enigma and may represent one or more previously unrecognized diseases. We are attempting to discover the etiology of this disease. Evidence for the existence of an additional water-borne hepatitis virus has come from our seroepidemiologic studies in India, Egypt and Saudi Arabia. We are attempting to transmit an agent from such patients. Hepatitis E virus may be emerging as a greater public health problem than previously thought. We are studying its epidemiology in developing and industrialized countries worldwide. Serologic evidence of infection of swine with hepatitis E virus (HEV) was obtained. A new and unique HEV strain was recovered from infected swine and characterized. It was shown to have a worldwide distribution. Seroepidemiological studies of swine handlers and matched blood donors have shown an excess of antibody to HEV in swine handlers, suggesting that the virus may be zoonotically spread. In addition, throughout FY 2009, we have been evaluating the significance of antibody to HEV (anti-HEV) in domestic animals that are part of the human food chain, especially cattle, sheep and goats. Anti-HEV has been found in all of the species, although not to the extent that it is found in swine. Rarely, swine are an important zoonotic source of hepatitis E, especially in industrialized countries, but these don't account for the high prevalence of anti-HEV in Islamic and Jewish cultures. In collaboration with XJ Meng, we are determining the susceptibility of goats to infection with the recognized HEV strains and attempting to recover HEV-like agents from young goats that are being intensively monitored for serologic and molecular evidence of infection. Similar serologic evidence for infection of wild rats with HEV has also been obtained and the infecting agent is being sought. To date we have successfully transmitted the agent from rats trapped in Los Angeles to laboratory rats of the same species (Rattus norvegicus). However, transmission was difficult, suggesting that the virus replicates at low titer. Modern techniques of molecular biology have been used to discover new viruses in recent years. These are now being applied to sera from patients with transfusion-associated or community-acquired hepatitis in a search for new hepatitis viruses that may cause up to 2% of such hepatitis in the US and up to one-third of hepatitis in developing countries. In addition, a significant number of cases of chronic hepatitis, cirrhosis and liver cancer remain undiagnosed. In an attempt to increase the sensitivity of virus discovery, we are applying microarray technology to attempts to transmit new agents to chimpanzees, the only species other than man that is susceptible to all five recognized human hepatitis viruses. Preliminary results are promising. Similarly, approximately one half of nonbacterial gastroenteritis cases have no recognized etiology. In collaboration with the Epidemiology Section, LID, we are applying the same approaches to attempts to identify new gastroenteritis agents. Kawasaki Disease is a life-threatening illness of young children. It has the epidemiologic characteristics of an infectious disease. The HVS and MHS have attempted to transmit a putative agent from acute phase clinical samples of children with Kawasaki Disease to chimpanzees. Preliminary results were promising but confirmatory studies have been negative, possibly because available chimpanzees may have been exposed to the putative agent of Kawasaki disease previously. In FY 2009, while evaluating the innate and adaptive immune responses of chimpanzees that had been experimentally infected with hepatitis E virus (HEV), we discovered an aberrant innate immune response in two chimpanzees that had been infected with HEV from an outbreak of hepatitis E in Pakistan. Based on extensive experience with innate and adaptive immune responses to all five recognized human hepatitis viruses in chimpanzees, we postulated that the response in these animals was to a second agent replicating in the liver. By attempting transmission from the second innate immune response episode to new chimpanzees, we demonstrated evidence for an infection not related to hepatitis E in the original infection. We are in the process of examining an additional passage of this putative agent in chimpanzees. It has been associated with only minor biochemical evidence of hepatitis, but that is also true for HEV infection of chimpanzees. We plan to determine if this putative agent produces more severe infection on serial passage and whether it can be associated with hepatitis or other liver disease, such as liver cancer. Liver cancer is a common sequela of infection with three of the five recognized human hepatitis viruses.

目前正在研究急性或慢性非甲、B、C、D、E型肝炎是否存在传染因子的生物学、血清学或分子学证据。暴发性非甲至戊型肝炎仍然是一个诊断上的谜，可能代表一种或多种以前未被认识的疾病。我们正试图找出这种疾病的病因。我们在印度、埃及和沙特阿拉伯进行的血清流行病学研究提供了存在另一种水传播肝炎病毒的证据。我们正试图从这样的病人身上传播一种病原体。戊型肝炎病毒可能正在成为比以前认为的更大的公共卫生问题。 我们正在全世界发展中国家和工业化国家研究其流行病学。 获得了戊型肝炎病毒（HEV）感染猪的血清学证据。从感染的猪中回收了一种新的独特的戊型肝炎病毒株，并对其进行了表征。 它被证明有一个世界性的分布。对猪处理者和匹配的献血者的血清流行病学研究表明，猪处理者中存在过量的HEV抗体，表明该病毒可能是动物源性传播的。此外，在整个2009财年，我们一直在评估作为人类食物链一部分的家畜，特别是牛、绵羊和山羊中HEV抗体（抗HEV）的意义。 在所有物种中都发现了抗HEV，尽管没有达到在猪中发现的程度。 很少，猪是戊型肝炎的重要人畜共患病来源，特别是在工业化国家，但这些并不能解释伊斯兰和犹太文化中抗HEV的高流行率。 与XJ Meng合作，我们正在确定山羊对已识别的HEV毒株感染的易感性，并试图从正在密切监测感染的血清学和分子证据的年轻山羊中回收HEV样因子。 也获得了野生大鼠感染戊型肝炎病毒的类似血清学证据，并正在寻找感染因子。到目前为止，我们已经成功地将这种病原体从洛杉矶的老鼠身上传播到同一物种的实验室老鼠（褐家鼠）身上。然而，传播是困难的，这表明病毒以低滴度复制。 近年来，现代分子生物学技术已被用于发现新病毒。目前，这些方法正应用于输血相关性肝炎或社区获得性肝炎患者的血清，以寻找可能导致美国高达2%的此类肝炎和发展中国家高达三分之一的肝炎的新肝炎病毒。此外，大量慢性肝炎、肝硬化和肝癌病例仍未得到诊断。 为了提高病毒发现的敏感性，我们正在应用微阵列技术，试图将新的病原体传播给黑猩猩，黑猩猩是除人类以外唯一对所有五种公认的人类肝炎病毒易感的物种。初步结果是有希望的。同样，大约一半的非细菌性胃肠炎病例没有公认的病因。 我们与LID流行病学科合作，采用相同的方法来尝试识别新的胃肠炎病原体。 川崎是一种危及幼儿生命的疾病。它具有传染病的流行病学特征。HVS和MHS试图将一种来自川崎患儿急性期临床样本的假定病原体传播给黑猩猩。初步结果是有希望的，但验证性研究一直是负面的，可能是因为现有的黑猩猩可能已经暴露于川崎病的推定代理人以前。 在2009财政年度，在评估实验感染戊型肝炎病毒（HEV）的黑猩猩的先天性和适应性免疫反应时，我们发现在巴基斯坦爆发戊型肝炎时感染HEV的两只黑猩猩中存在异常的先天性免疫反应。 基于黑猩猩对所有五种公认的人类肝炎病毒的先天性和适应性免疫反应的广泛经验，我们假设这些动物的反应是对肝脏中复制的第二种因子的反应。 通过尝试从第二次先天免疫反应事件传播到新的黑猩猩，我们证明了在原始感染中与戊型肝炎无关的感染的证据。 我们正在研究黑猩猩体内这种假定因子的另一个通道。 它只与肝炎的轻微生化证据有关，但黑猩猩的HEV感染也是如此。 我们计划确定这种假定的病原体是否在连续传代时产生更严重的感染，以及它是否与肝炎或其他肝脏疾病（如肝癌）有关。 肝癌是感染五种公认的人类肝炎病毒中的三种病毒后的常见后遗症。