Characterization of a Novel Transcriptional Regulator, NCOA7, and its Protective Role during Acute Systemic Salmonella Infection

Megan M. Eva1,4, Kyoko E. Yuki1,4, Hyunwoo Kwon5, Jeremy A. Schwartzentruber1,6, Shauna M. Dauphinee1,4, Mark Lathrop1,6, Jacek Majewski1,6, Silvia M. Vidal1,2,3, Michael R. Volkert7, Samantha Gruenheid3,4, Peter L. Oliver8, John H. Brumell5 and Danielle Malo1,2,4

Departments of 1. Human Genetics, 2. Medicine, 3. Microbiology and Immunology, 4. Complex Traits Group, McGill University, Montreal, QC, Canada; 5. Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada; 6. McGill University and Genome Québec Innovation Centre, Montreal, QC, Canada; 7. Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA, USA; 8. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

Salmonella Typhimurium (ST) is a ubiquitous Gram-negative intracellular bacterium that causes both food and waterborne illnesses: localized gastroenteritis, systemic enteric fever, or chronic disease. The host response to infection requires direct or indirect bacterial sensing, activation of transcriptional programs directing innate and specific immunity, as well as communication between immune cells and with distal organs. Severity of infection however depends on the integration of multiple factors including bacterial virulence, environmental cues, and host genetic determinants.

We used a forward genomics approach by ENU germline mutagenesis to identify previously unknown immune genes critical in the response to systemic ST infection in mice. From this screen phenotyping for survival following IV infection, we identified the deviant pedigree (Ity17) with increased susceptibility to ST infection. Using linkage analysis and exome sequencing we further identified a mutation in Nuclear Receptor Coactivator 7 (Ncoa7) within our mapped 4.8 Mb interval on chromosome 10. Homozygous mutant mice present with increased hepatosplenic bacterial load albeit with no associated atypical tissue pathology or inflammation during ST infection. Genome-wide expression analysis between wild-type and mutant mice during infection revealed deregulated transcriptional responses associated with GO terms including cell cycle, DNA metabolic process, and antigen processing and presentation.

NCOA7 was initially identified as a transcriptional coactivator of various nuclear receptors (ERα, TRβ, RARα, and PPARγ). Moreover, NCOA7 as well as a recently identified IFN-regulated alternative transcript, NCOA7-AS, was also shown to be protective against oxidative stress and downstream DNA damage. Interestingly, homozygous mutant mice present with decreased Ncoa7-as expression in tissues after infection. We are investigating NCOA7 functions in regulating transcription of immune targets, metabolism and oxidation resistance as possible mechanisms to control ST infection.