HPMI: Host Pathogen Mapping Initiative

宿主病原体图谱倡议： 国家传染病系统生物学研究中心 疾病 总体总结 当我们面临回归的现实时，抗生素耐药性病原体不再是“新兴”威胁 在抗生素出现之前的时代，对最简单的微生物感染的治疗是无效的。中心 疾病控制与预防 (CDC) 估计超过 200 万人感染了严重的耐药菌 每年，细菌感染都会导致至少 23,000 人死亡。这些数字将急剧增加 我们抵抗这些感染的能力减弱了。不幸的是，还没有新类别的抗生素 自 20 世纪 60 年代以来就被发现，强调了这样一个事实：开发新颖的方法需要新颖的方法 治疗感染的疗法。由于这些事实，人们现在认识到，努力发展 治疗传染病的宿主导向疗法可能具有独特的优势。另外，最近的工作还有 研究表明，虽然相似的蛋白质可能不会被不同的病原体靶向，但相同的功能 在感染过程中，通路经常被劫持和重新连接。由于这些原因，研究 传染病越来越依赖于多种类型的生物网络的知识， 包括蛋白质之间的物理相互作用以及基因之间的合成致死和上位相互作用， 允许解构功能途径。 在此，我们寻求对一项名为“宿主病原体图谱计划”(HPMI) 的新努力的支持 （http://www.hpmi.ucsf.edu），旨在全面详细说明致病菌之间复杂的相互作用 基因和蛋白质及其在感染过程中劫持和重新连接的宿主因子。 HPMI 是一个 加州大学的多校区倡议，以加州大学旧金山分校和加州大学伯克利分校为中心， 利用先进的网络测绘、计算分析和传染病研究平台 由多名 HPMI 研究人员在过去十年中开发。因此，这些平台将转向 有效地生成、组装和分析宿主-病原体分子网络，以期利用它 临床环境中的信息。 未来五年，HPMI 将寻求通过以下方式促进发病机制研究的重大相变： (1) 使用来自三个的分泌蛋白组全面绘制物理相互作用的网络 细菌；结核分枝杆菌 (Mtb)、金黄色葡萄球菌 (SA) 和沙眼衣原体 (CT) 它们的宿主，揭示这些病原体针对的蛋白质复合物和高阶分子单元； (2) 绘制目标基因之间合成致死和上位相互作用的并行网络 细菌，揭示发病机制的功能逻辑； (3) 建立稳健的计算 用于组装和使用宿主-病原体网络图的方法、最终用户软件和数据库 基本和临床模式； (4) 在全球范围内培养一批领先的传染病研究人员 将 HPMI 扩展为全球协调伙伴关系； (5) 培训当前和下一代 网络生物学及其在传染病研究中的应用的科学家。

THE HOST PATHOGEN MAP INITIATIVE: A NATIONAL RESEARCH CENTER FOR SYSTEMS BIOLOGY OF INFECTIOUS DISEASE OVERALL SUMMARY Antibiotic-resistant pathogens are no longer an “emerging” threat as we face the reality of a return to the pre-antibiotic age where treatments for the simplest microbial infections are ineffective. The Centers for Disease Control and Prevention (CDC) estimates that more than 2 million people acquire a serious resistant bacterial infection each year, and at least 23,000 deaths result. These numbers will increase dramatically as our ability to fight these infections diminishes. Unfortunately, there have been no novel classes of antibiotics discovered since the 1960s, underscoring the fact that novel approaches are required to develop novel therapies to treat infection. As a result of these facts, it is now being realized that efforts to develop host-directed therapies to treat infectious diseases may have unique advantages. Also, recent work has revealed that although similar proteins may not be targeted by different pathogens, the same functional pathways are often hijacked and re-wired during the course of infection. For these reasons, the study of infectious disease is becoming increasingly dependent on knowledge of biological networks of multiple types, including physical interactions among proteins and synthetic-lethal and epistatic interactions among genes, which allow for deconstruction of functional pathways. Here we seek support for a new effort, termed The Host Pathogen Map Initiative (HPMI) (http://www.hpmi.ucsf.edu), aimed at comprehensively detailing the complex interactions among pathogenic genes and proteins with the host factors they hijack and rewire during the course of infection. The HPMI is a multi-campus initiative of the University of California, centered at UC San Francisco and UC-Berkeley, which leverages advanced network mapping, computational analysis and infectious disease research platforms developed by multiple HPMI investigators over the past decade. Thus primed, these platforms will be turned to efficiently generate, assemble, and analyze host-pathogen molecular networks with a view towards using this information in a clinical setting. Over the next five years, the HPMI will seek to catalyze major phase transitions in pathogenesis research by (1) Comprehensively mapping the networks of physical interactions using sets of secreted proteins from three bacteria; Mycobacterium tuberculosis (Mtb), Staphylococcus aureus (SA) and Chlamydia trachomatis (CT) with their host, revealing the protein complexes and higher-order molecular units targeted by these pathogens; (2) Mapping the parallel networks of synthetic-lethal and epistatic interactions among the genes being targeted by the bacteria, revealing the functional logic of pathogenesis; (3) Establishing the robust computational methodology, end-user software, and databases for assembly and use of host-pathogen network maps in both basic and clinical modalities; (4) Building a critical mass of leading infectious disease investigators worldwide to expand HPMI into a global coordinated partnership; and (5) Training the current and next-generation of scientists in Network Biology and its applications to infectious disease research.