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.

OVERALL NARRATIVE Although much attention has been devoted to developing therapeutic approaches that specifically target pathogenic organisms, work must also be done to uncover host-directed therapies. To accomplish this, it is critical to understand the many interactions between the pathogenic genes and proteins hijack and re-wire the host machinery during infection. The Host Pathogen Map Initiative will apply systematic approaches to comprehensively map the molecular networks that underlie pathogenesis and will use these maps as a key resource for novel therapies.