Pan-Genomic Approaches for Comprehensive Screening of Novel or Emerging Infectious Agents in Blood Emerging infectious agents, the latest of which is Zika virus, continually threaten the safety of the 15 million transfusions performed annually in the United States, yet the lack of diagnostic tools to comprehensively test for all bloodborne pathogens or to identify infections from novel viruses has greatly hindered surveillance efforts. In a previous grant, we have pioneered the development of microarray and metagenomic sequencing-based approaches to comprehensively screen blood for both known and novel pathogens, and have identified a number of novel viruses circulating in human blood. We have established long-term collaborations with national and international collaborators who will provide us with clinical and donor blood samples from individuals infected with chikungunya, dengue, Ebola, Zika, Lassa, and West Nile virus, as well as non-viral pathogens (e.g. Babesia microti and Plasmodium falciparum), for analysis. This project proposes (1) to develop an accurate and comprehensive yet practical sequencing-based platform (BloodSeq) for simultaneous detection and whole-genome characterization of all American Association of Blood Banks (AABB)-priority pathogens in infected patients and blood donations, (2) to discover and further describe the epidemiology and potential pathogenicity of novel infectious viruses that pose a potential threat of bloodborne transmission, and (3) to define complementary host response biosignatures for transfusion-transmissible pathogens using transcriptome profiling, especially in asymptomatic infected donors. A key deliverable from this 5-year project will be implementation of the BloodSeq platform by public health agencies such as the American Red Cross for comprehensive bloodborne pathogen screening of the blood supply.The results from these studies will advance genomic sequencing technologies as validated screening tools to ensure transfusion safety, with significant clinical and public health implications.