The overall goal of this endeavor is to establish the Candidate as an independent scientific investigator through a carefully designed combination of career development activities and directed translational research. This project aims to define patterns of host gene expression which are capable of accurately classifying acute upper respiratory viral infection (URI) as well as predicting eventual disease severity from URIs in a population of US Veterans. This work represents a unique opportunity to utilize data collected as a part of DARPA- funded respiratory viral challenge studies in young, healthy individuals as a starting point to define the initiation nd evolution of the human response to infection in a more vulnerable population in keeping with the mission of the Veterans Affairs Health System. The objective of this application is to test and refine (where necessary) the applicability of genomic signatures to a more varied population of older Veterans whose health status is more likely to be complicated by age and multiple comorbidities which may alter the nature of the genomic response. This will be accomplished through the following Specific Aims:
Aim 1. Derive host gene signatures that define upper respiratory viral infection in an aging population through use of an in vitro model. We will isolae and infect human Peripheral Blood Mononuclear Cells with influenza viruses in order to develop gene signatures which characterize infection. These PBMCs will be isolated from stable, non-acutely infected individuals selected from a population of US Veterans living in our Extended Care and Rehabilitation Center. The PBMCs will then be exposed in vitro to live respiratory viruses (Influenza, HRV, RSV) or bacteria (Streptococcus pneumoniae, Mycoplasma, or E. coli), and host RNA will be isolated at multiple timepoints and assayed by microarray for gene expression. Genomic signatures will then be analyzed through standard methods as well as by the modified sparse latent factor analysis we have previously developed for this purpose.
Aim 2. Enroll and characterize a cohort of US Veterans with URI We will identify cases of Influenza-like illness in US Veterans through two major portals. The first will be to identify cases of ILI among individuals living in the DVAMC ECRC. The second will be to capture individuals presenting with ILI through the DVAMC Emergency Department. In both cases we will obtain peripheral blood RNA for microarray analysis at the time of presentation as well as standard samples for both microbiological and serological diagnosis. These individuals will be followed with daily symptom score reporting - inpatients in the ECRC through daily visits from study staff, and outpatients enrolled in the ED through daily phone interviews. Subjects enrolled in the ECRC will also have blood drawn daily throughout the course of disease for RNA isolation and microarray analysis as well as cytokine expression in order to characterize the evolution of the host response.
Aim 3. Evaluate performance of URI gene signatures in an aging population. We will evaluate the performance of our genomic signatures identified a) in our previous studies with young, healthy volunteers and b) through our in vitro model of infection in Specific Aim 1 through application of these signatures to individuals who have presented with microbiologically proven Influenza infection as defined in Specific Aim 2.
Aim 4. Evaluate new gene signature(s) specific to an aging population. We will derive new gene signatures based upon the data from Influenza infected individuals enrolled in Aim 2. Given potential differences in the populations, we will the cross-validate signatures derived from ECRC patients on signatures derived from ED-enrolled patients and vice versa. Furthermore, we will utilize variations in gene signatures at the time of presentation to build a genomic prediction model for eventual disease severity.

Public Health Relevance

Upper respiratory infections (URIs) are among the most common causes of physician visits in the United States. In a given year Influenza alone affects from 5-20% of the population in the US, and in 2009 resulted in over 400,000 hospitalizations and over 18,000 deaths. In the period covering 2009-10 there were over 640,000 clinical URI-related visits recorded in the VA health system. URIs remain common among community-living persons and in addition to the health impact cause significant health-care and societal costs. Those particularly at risk include the elderly and individuals with chronic respiratory, cardiac or metabolic diseases. These viral illnesses all exhibit ease of communicability, morbidity with resultant loss of productivity, sever complicating diseases, and increased risk of death, particularly among the demographics which comprise much of the Veteran population. This proposal aims to identify new tests which are capable of more accurately diagnosing these diseases and predicting who is more likely to become severely ill.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (IK2)
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Special Emphasis - Research on Clinical Application of Genetics (SPLC)
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Durham VA Medical Center
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