William E Yang1, Sunil Suchindran2, Bradly P Nicholson3, Micah T McClain4, Thomas Burke2, Geoffrey S Ginsburg2, Clayton D Harro5, Subhra Chakraborty5, David A Sack5, Christopher W Woods4, Ephraim L Tsalik6. 1. Duke University School of Medicine, Department of Medicine, Duke University Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University. 2. Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University. 3. Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University Internal Medicine Service, Durham VA Medical Center, Duke University Medical Center, North Carolina. 4. Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University Internal Medicine Service, Durham VA Medical Center, Duke University Medical Center, North Carolina Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, North Carolina. 5. Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 6. Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, North Carolina Emergency Medicine Service, Durham VA Medical Center, North Carolina.
Abstract
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.
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.
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