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Cellular Polarity and Viral Infection

CHS Research Group Cellular Polarity and Viral Infection

Dr. Steeve Boulant

Colorectal cancer (CRC) is the third most common type of cancer worldwide. Its development is due to lifestyle choices, aging and in some cases genetic predispositions. Patients with inflammatory bowel disease (IBD) have a high risk of developing CRC. IBD has been linked with excessive inflammation in response to the microbiota. Intestinal epithelial cells (IECs) lining the surface of our gut have a very complicated dilemma. They must tolerate the presence of our commensal flora in the lumen of the gut while remaining responsive to fight enteric pathogen infection. Many studies have focused on the role that bacteria play in creating inflammation in the gut; however, viruses have been largely ignored. We believe that both enteric viruses and the anti-viral response generated by intestinal cells play an important role in controlling the inflammation and homeostasis state within the gut. In the lab we dissect the complex interactions between enteric viruses and polarized intestinal epithelial cells (IECs). Interferons (IFNs) are critical actors in innate immune defense against pathogens. Type I IFN is ubiquitous to all cells, whereas type III IFNs can only act on epithelial cells due to the restricted expression of their receptor. While looking for the molecular basis allowing the maintenance of the homeostatic state in healthy gut, we have found that similar subsets of IFN stimulated genes (ISGs) are produced upon type I and type III interferon treatment of IECs. However, the temporal expression of these genes is unique to each interferon and we believe that this functionally distinguishes both IFNs and is indispensable for the specific function of type III IFN at mucosal surfaces. We are elucidating the distinct type I vs. type III IFN signaling, in order to determine their role in the maintenance of gut homeostasis.

FUTURE OUTLOOK
Our future perspectives are to investigate the precise functions and mode of action of both type I and type III IFNs. We are exploiting organoid mini-gut culture systems derived from human intestinal stem cells to study how human gut homeostasis is achieved and maintained. We are currently performing a systematic proteomic and genomic analysis of these mini-guts treated with either type I or type III IFNs in order to identify the key regulators that are differently functionalized by these two IFNs. Ultimately, we aim at understanding how dysregulation of this perfectly tuned immune system leads to inflammation, disease and cancer development.

Contact

Dr. Steeve Boulant
Cellular Polarity and Viral Infection (F140)

CHS Research Group at CellNetworks Heidelberg University and DKFZ
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 344
69120 Heidelberg

Tel: +49 6221 56-7858
E-Mail: s.boulant@dkfz.de

Selected Publications

  • Stanifer, M.L. et al. (2016). Reovirus intermediate subviral particles constitute a strategy to infect intestinal epithelial cells by exploiting TGF-? particles dependent pro-survival signaling. Cell Microbiol, in press.
  • Odendall C, et al. (2014). Diverse intracellular pathogens activate type III interferon expression from peroxisomes. Nat Immunol, 15(8), 717-726.
  • Boulant S, et al. (2013). Similar uptake but different trafficking and escape routes of reovirus virions and infectious subvirion particles imaged in polarized Madin-Darby canine kidney cells. Mol. Biol. Cell, 24(8), 1196-1207.
  • Dixit E, et al. (2010). Peroxisomes are signaling platforms for antiviral innate immunity. Cell, 141(4), 668-81.
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