Browsing by Author "Burke, Thomas"

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    A Genomic Signature of Influenza Infection Shows Potential for Presymptomatic Detection, Guiding Early Therapy, and Monitoring Clinical Responses.
    (Open Forum Infect Dis, 2016-01) McClain, Micah T; Nicholson, Bradly P; Park, Lawrence P; Liu, Tzu-Yu; Hero, Alfred O; Tsalik, Ephraim L; Zaas, Aimee K; Veldman, Timothy; Hudson, Lori L; Lambkin-Williams, Robert; Gilbert, Anthony; Burke, Thomas; Nichols, Marshall; Ginsburg, Geoffrey S; Woods, Christopher W
    Early, presymptomatic intervention with oseltamivir (corresponding to the onset of a published host-based genomic signature of influenza infection) resulted in decreased overall influenza symptoms (aggregate symptom scores of 23.5 vs 46.3), more rapid resolution of clinical disease (20 hours earlier), reduced viral shedding (total median tissue culture infectious dose [TCID50] 7.4 vs 9.7), and significantly reduced expression of several inflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin-6, and others). The host genomic response to influenza infection is robust and may provide the means for early detection, more timely therapeutic interventions, a meaningful reduction in clinical disease, and an effective molecular means to track response to therapy.
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    Host gene expression classifiers diagnose acute respiratory illness etiology.
    (Sci Transl Med, 2016-01-20) Tsalik, Ephraim L; Henao, Ricardo; Nichols, Marshall; Burke, Thomas; Ko, Emily R; McClain, Micah T; Hudson, Lori L; Mazur, Anna; Freeman, Debra H; Veldman, Tim; Langley, Raymond J; Quackenbush, Eugenia B; Glickman, Seth W; Cairns, Charles B; Jaehne, Anja K; Rivers, Emanuel P; Otero, Ronny M; Zaas, Aimee K; Kingsmore, Stephen F; Lucas, Joseph; Fowler, Vance G; Carin, Lawrence; Ginsburg, Geoffrey S; Woods, Christopher W
    Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational cohort study determined whether host gene expression patterns discriminate noninfectious from infectious illness and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or noninfectious illness, as well as 44 healthy controls, was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a noninfectious cause of illness (26 probes). Overall accuracy was 87% (238 of 273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, P < 0.03) and three published classifiers of bacterial versus viral infection (78 to 83%). The classifiers developed here externally validated in five publicly available data sets (AUC, 0.90 to 0.99). A sixth publicly available data set included 25 patients with co-identification of bacterial and viral pathogens. Applying the ARI classifiers defined four distinct groups: a host response to bacterial ARI, viral ARI, coinfection, and neither a bacterial nor a viral response. These findings create an opportunity to develop and use host gene expression classifiers as diagnostic platforms to combat inappropriate antibiotic use and emerging antibiotic resistance.
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    Transcriptomic Analysis of the Host Response and Innate Resilience to Enterotoxigenic Escherichia coli Infection in Humans.
    (J Infect Dis, 2016-05-01) Yang, William E; Suchindran, Sunil; Nicholson, Bradly P; McClain, Micah T; Burke, Thomas; Ginsburg, Geoffrey S; Harro, Clayton D; Chakraborty, Subhra; Sack, David A; Woods, Christopher W; Tsalik, Ephraim L
    BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is a globally prevalent cause of diarrhea. Though usually self-limited, it can be severe and debilitating. Little is known about the host transcriptional response to infection. We report the first gene expression analysis of the human host response to experimental challenge with ETEC. METHODS: We challenged 30 healthy adults with an unattenuated ETEC strain, and collected serial blood samples shortly after inoculation and daily for 8 days. We performed gene expression analysis on whole peripheral blood RNA samples from subjects in whom severe symptoms developed (n = 6) and a subset of those who remained asymptomatic (n = 6) despite shedding. RESULTS: Compared with baseline, symptomatic subjects demonstrated significantly different expression of 406 genes highlighting increased immune response and decreased protein synthesis. Compared with asymptomatic subjects, symptomatic subjects differentially expressed 254 genes primarily associated with immune response. This comparison also revealed 29 genes differentially expressed between groups at baseline, suggesting innate resilience to infection. Drug repositioning analysis identified several drug classes with potential utility in augmenting immune response or mitigating symptoms. CONCLUSIONS: There are statistically significant and biologically plausible differences in host gene expression induced by ETEC infection. Differential baseline expression of some genes may indicate resilience to infection.