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 抗药性病原体不再是一个正在出现的威胁，因为我们面临着回归到 抗生素之前的时代，对最简单的微生物感染的治疗是无效的。城市发展中心 疾病控制和预防中心(CDC)估计，超过200万人获得了严重的耐药性 细菌感染每年造成至少23,000人死亡。这些数字将大幅增加，因为 我们对抗这些感染的能力就会减弱。不幸的是，目前还没有新的抗生素类别。 自20世纪60年代以来被发现，强调了发展小说需要新颖的方法这一事实 治疗感染的疗法。由于这些事实，人们现在认识到，发展的努力 宿主导向疗法治疗传染病可能有独特的优势。此外，最近的工作已经 揭示了尽管相似的蛋白质可能不是不同病原体的靶标，但相同的功能 在感染过程中，通路经常被劫持和重新布线。基于这些原因，研究 传染病正变得越来越依赖多种类型生物网络的知识， 包括蛋白质之间的物理相互作用和基因之间的合成致死和上位性相互作用， 这允许解构功能通路。 在这里，我们寻求对一项名为宿主病原体图谱倡议(HPMI)的新努力的支持 (http://www.hpmi.ucsf.edu)，旨在全面详细地描述致病菌之间的复杂相互作用 基因和蛋白质与宿主因子一起，在感染过程中被劫持和重新连接。HPMI是一种 加州大学多校区计划，以加州大学旧金山分校和加州大学伯克利分校为中心， 利用先进的网络映射、计算分析和传染病研究平台 由多名HPMI调查人员在过去十年开发的。因此，这些平台将被转向 高效地生成、组装和分析宿主-病原体分子网络，以期利用这一点 临床环境中的信息。 在接下来的五年里，HPMI将通过以下方式寻求催化发病机制研究中的主要阶段转变 (1)使用三组分泌蛋白质全面绘制物理相互作用网络 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，揭示了这些病原体靶向的蛋白质复合体和更高阶分子单元；(2) 绘制目标基因之间的合成致死和上位性相互作用的平行网络 细菌，揭示了发病的功能逻辑；(3)建立了健壮的计算 用于组装和使用两者中的宿主-病原体网络图的方法、终端用户软件和数据库 基本和临床模式；(4)在世界范围内建立一大批领先的传染病研究人员 将HPMI扩展为全球协调伙伴关系；以及(5)培训当前和下一代 网络生物学科学家及其在传染病研究中的应用。

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.