877. Transcriptomic Analysis of the Host Response to Enterotoxigenic E. coli (ETEC) Infection in Humans
Session: Poster Abstract Session: Bacterial Infections: Pathogenesis and Immunity
Friday, October 9, 2015
Room: Poster Hall
Posters
  • ETECPoster_v10.pdf (524.7 kB)
  • Background: Enterotoxigenic Escherichia coli(ETEC) is a globally prevalent cause of diarrheal disease. 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 H10407.

    Methods: Thirty healthy adults without history of ETEC infection for two years prior were enrolled and challenged with ETEC H10407.  In our gene expression analyses, we focused on those developing severe symptoms (n=6) and matching asymptomatic subjects (n=6).  Blood samples were collected for transcriptomic analysis at baseline (eight hours after challenge) and daily until discharge, approximately eight days after challenge.  Gene expression was characterized using Affymetrix microarrays, and dimension reduction and methods for longitudinal analysis were used for statistical analyses.  ToppFun and Broad Institute’s CMap were used to gain functional insight into the transcriptomic findings.

    Results: Compared to baseline, subjects with severe symptoms demonstrated significantly different expression of 406 genes. Functional annotation revealed immune response, protein synthesis, and cellular processes.  These subjects also had a differential response of 327 genes, primarily associated with immune response, when compared with asymptomatic subjects both at the time of peak symptoms and longitudinally over the time course.  Connectivity Map analysis suggested similarity between ETEC infection and NF-kB inhibitors, protein synthesis inhibitors, typical antipsychotics, and zinc-dependent histone deacetylase inhibitors.  A comparison of symptomatic and asymptomatic subjects also revealed a 29 gene signature suggesting a susceptibility to infection.  Of these 29 genes, C4BPA and GZMH have known involvement in infection response, and LGALS8, TAP2, and WARS have been implicated in susceptibility to other infections.

    Conclusion: 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 ETEC infection.

    William E. Yang, BS1,2, Sunil Suchindran, PhD2, Bradly P. Nicholson, PhD2,3, Micah T. McClain, MD, PhD2,4, Thomas Burke, PhD2, Geoffrey S. Ginsburg, MD, PhD2, Clayton D. Harro, MD, ScM5, Subhra Chakraborty, MPH, PhD5, David A. Sack, MD5, Christopher W. Woods, MD, MPH, FIDSA2,6 and Ephraim L. Tsalik, MD, PhD2,7, (1)Duke University School of Medicine, Durham, NC, (2)Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC, (3)Durham VA Medical Center, Durham, NC, (4)Internal Medicine/Division of Infectious Diseases, Duke University Medical Center, Durham, NC, (5)Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, (6)Global Health, Medicine, Duke University, Durham, NC, (7)Emergency Medicine Service, Durham VA Medical Center, Durham, NC

    Disclosures:

    W. E. Yang, None

    S. Suchindran, None

    B. P. Nicholson, None

    M. T. McClain, None

    T. Burke, None

    G. S. Ginsburg, None

    C. D. Harro, None

    S. Chakraborty, None

    D. A. Sack, None

    C. W. Woods, None

    E. L. Tsalik, None

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 7th with the exception of research findings presented at the IDWeek press conferences.