SUMMARY/ABSTRACT The objective of this proposal is to deploy standard as well as innovative diagnostic tools in order to investigate what proportion of severe febrile illness (SFI) in northern Tanzania is attributable to emerging zoonotic viral pathogens. Fever is among the most common reasons for seeking health care in less developed countries, yet up to half of patients hospitalized with fever in sub-Saharan Africa may go without a laboratory- confirmed diagnosis—this represents a serious knowledge gap that hinders disease prevention efforts. Prior research in northern Tanzania has revealed that animal-borne bacterial infections are a common cause of SFI, perhaps reflecting the effects of close interaction between humans, livestock and wildlife in many parts of sub- Saharan Africa. Yet the impact of animal-borne viral infections, such as henipa-, bunya-, corona- and reoviruses, remains unknown. An enhanced understanding of whether and which of these high-consequence viral pathogens are causing SFI is fundamental to the prevention and control of severe infectious diseases in sub-Saharan Africa and to the global health security agenda of the United States and other G7 countries. To these ends, this career development award proposes to utilize well-characterized archived blood specimens from prior fever etiology research in northern Tanzania in order to undertake the following SPECIFIC AIMS: SPECIFIC AIM 1—Establish the prevalence of exposure to zoonotic viral pathogens by performing antibody evaluations of serum from patients with SFI and from previously enrolled community-dwellers. SPECIFIC AIM 2— Establish the proportion of SFI cases with detectable viremia from select zoonotic pathogens by performing real-time polymerase chain reaction (PCR) assays on SFI patient blood samples. SPECIFIC AIM 3—Achieve enhanced viral pathogen detection and discover new viral pathogens by interrogating SFI blood samples with hybridization enrichment next-generation sequencing technology. The requisite laboratory work to achieve these SPECIFIC AIMS will be conducted at Duke-National University of Singapore Graduate Medical School (Duke-NUS) under the direction of the Candidate and the Director of the Duke-NUS Program in Emerging Infectious Disease, Lin-Fa Wang, PhD (K23 Co-Mentor), and Duke University/Duke-NUS faculty, Greg Gray, MD, MPH (K23 Co-Mentor). De-identified serum, plasma and whole blood will be utilized for these aims. These well-characterized blood specimens represent nearly 1500 patients enrolled in two febrile illness research cohorts conducted in northern Tanzania by K23 Primary Mentor, John Crump, MB ChB, MD: International Co-Studies of AIDS-Associated Co-Infections (U01 AI062563), a comprehensive fever etiology study; and The Impact and Social Ecology of Bacterial Zoonoses in Northern Tanzania (R01TW009237), an epidemiologic risk factor analysis on zoonotic causes of SFI. The Candidate, Matthew Rubach, MD, is a board-certified medical microbiolo...