Early diagnosis of systemic infection in humans and prediction of clinical outcome both remain elusive, despite the critical need for both. The two basic approaches for diagnosis and prognosis, direct identification of the infectious agent and measurement of host response features, have been limited by reliance on cultivation, pre-test assumptions about specific agents, limited breadth of coverage, and an insufficient signal-to-noise ratio. Recent advances in DNA sequencing technology and computational tools for data analysis provide new opportunities for characterizing complex mixtures of DNA and RNA molecules in a minimally-biased fashion, and for detecting rare sequences of interest in clinical specimens. The goals of this project are to characterize microbial and viral genomic sequences in the peripheral blood of healthy subjects, as well as subjects with fever (and in some cases, known causative infectious agents) at the time of clinical presentation, to characterize human genome-wide RNA patterns in peripheral blood, and then to integrate these complementary forms of data so as to derive putative diagnostic and prognostic signatures for systemic infection. We propose three aims;(1) characterize microbial and viral sequences and host RNAs in peripheral blood of non-febrile, healthy subjects;(2) characterize microbial and viral sequences and host RNAs in human blood during febrile illness;and (3) identify and validate diagnostic and prognostic biomarkers during early stages of febrile illness based on microbial and viral sequences, host RNAs, and clinical features. Our long-term objectives are to validate novel early diagnostic and prognostic signatures for several classes and species of pathogens and their related clinical syndromes, with attention to early predictors of subsequent critical illness requiring intensive care. Sequence-based signatures will serve as the basis for the design of probes on CMOS electrochemical-based active microarrays and other technologies, so that they can be exploited and deployed at the point-of-care in an easy-to-use format.
Early diagnosis of systemic infection in humans and prediction of clinical outcome both remain elusive, despite the critical need for both. We propose to employ state of the art techniques for characterizing microbial and viral DNA and RNA in human blood, as well as host molecules that are expressed early during the course of infection, in order to identify and then validate genetic signatures. These signatures will serve as the basis for tests that reveal the nature of the causative agent as well as the likely outcome of the disease early, when opportunities for beneficial intervention are greatest.
|Lindow, Janet C; Wunder Jr, Elsio A; Popper, Stephen J et al. (2016) Cathelicidin Insufficiency in Patients with Fatal Leptospirosis. PLoS Pathog 12:e1005943|
|Bouilly, Delphine; Hon, Jason; Daly, Nathan S et al. (2016) Single-Molecule Reaction Chemistry in Patterned Nanowells. Nano Lett 16:4679-85|
|Bacharach, Eran; Mishra, Nischay; Briese, Thomas et al. (2016) Characterization of a Novel Orthomyxo-like Virus Causing Mass Die-Offs of Tilapia. MBio 7:e00431-16|
|Beall, Anne; Yount, Boyd; Lin, Chun-Ming et al. (2016) Characterization of a Pathogenic Full-Length cDNA Clone and Transmission Model for Porcine Epidemic Diarrhea Virus Strain PC22A. MBio 7:e01451-15|
|Forero, Adriana; Tisoncik-Go, Jennifer; Watanabe, Tokiko et al. (2016) The 1918 Influenza Virus PB2 Protein Enhances Virulence through the Disruption of Inflammatory and Wnt-Mediated Signaling in Mice. J Virol 90:2240-53|
|Tisoncik-Go, Jennifer; Gasper, David J; Kyle, Jennifer E et al. (2016) Integrated Omics Analysis of Pathogenic Host Responses during Pandemic H1N1 Influenza Virus Infection: The Crucial Role of Lipid Metabolism. Cell Host Microbe 19:254-66|
|Warren, Steven B; Vernick, Sefi; Romano, Ethan et al. (2016) Complementary Metal-Oxide-Semiconductor Integrated Carbon Nanotube Arrays: Toward Wide-Bandwidth Single-Molecule Sensing Systems. Nano Lett 16:2674-9|
|Strouts, Fiona R; Popper, Stephen J; Partidos, Charalambos D et al. (2016) Early Transcriptional Signatures of the Immune Response to a Live Attenuated Tetravalent Dengue Vaccine Candidate in Non-human Primates. PLoS Negl Trop Dis 10:e0004731|
|Menachery, Vineet D; Yount Jr, Boyd L; Sims, Amy C et al. (2016) SARS-like WIV1-CoV poised for human emergence. Proc Natl Acad Sci U S A 113:3048-53|
|Tokarz, Rafal; Sameroff, Stephen; Hesse, Richard A et al. (2015) Discovery of a novel nidovirus in cattle with respiratory disease. J Gen Virol 96:2188-93|
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