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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University
New York
United States
Zip Code
Rosenstein, Jacob K; Lemay, Serge G; Shepard, Kenneth L (2015) Single-molecule bioelectronics. Wiley Interdiscip Rev Nanomed Nanobiotechnol 7:475-93
Tokarz, Rafal; Williams, Simon Hedley; Sameroff, Stephen et al. (2014) Virome analysis of Amblyomma americanum, Dermacentor variabilis, and Ixodes scapularis ticks reveals novel highly divergent vertebrate and invertebrate viruses. J Virol 88:11480-92
Rasmussen, Angela L; Okumura, Atsushi; Ferris, Martin T et al. (2014) Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance. Science 346:987-91
Uccellini, Lorenzo; Ossiboff, Robert J; de Matos, Ricardo E C et al. (2014) Identification of a novel nidovirus in an outbreak of fatal respiratory disease in ball pythons (Python regius). Virol J 11:144
Menachery, Vineet D; Debbink, Kari; Baric, Ralph S (2014) Coronavirus non-structural protein 16: evasion, attenuation, and possible treatments. Virus Res 194:191-9