Importance of the intestinal hypoxic environment in regulating host-enteric virus interactions

• Applicant: Zina Maria Uckeley, Ph.D.
• Subject Area: Virology ; Immunology ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521582111

Pathogenic enteric viruses (e.g., rotavirus) are of major clinical importance as they cause a great fraction of pediatric diarrheal cases globally and can lead to life threatening infections in immunocompromised patients. Intestinal epithelial cells constitute the primary barrier that enteric viruses need to overcome to initiate infection. They are organized in discrete crypt-villi structures with stem cells located in the crypt region and the most differentiated cells (e.g., enterocytes) at the tip of the villi. A steep oxygen gradient exists along the crypt-villi structure placing the crypts under “normal” oxygen level (normoxia) and the tips of the villi under very low oxygen levels (hypoxia). While hypoxia is known to be critical for a healthy commensal microbiota and for regulating inflammation during inflammatory bowel disease flare-ups, it remains unknown how hypoxia impacts infection of intestinal epithelial cells by enteric viruses.The focus of this application is to exploit the human enteric pathogen rotavirus, human intestinal organoids, and in vivo mouse models to fill this gap of knowledge. My host laboratory has discovered that hypoxia negatively impacts the intrinsic innate immune response generated by intestinal epithelial cells upon infection. Hypoxia impairs interferon production and concomitantly, enteric virus replication increases. The Boulant group could show that this hypoxia-mediated inhibition of immune response is restricted to the tip of the villi. Histological characterization of human and mice intestinal tracts infected with rotavirus reveal that rotavirus infection is mostly localized to the tip of the villi. As such, I hypothesize that the oxygen gradient present in the crypt-villi structures contributes to the spatial restriction of enteric virus infection to the tip by impairing the potency of the interferon response. Additionally, the Boulant team has gathered evidence that stem cells and differentiated cells differently respond to hypoxia. I hypothesize that this differential response is critical to maintain gut homeostasis as it allows better protection of the stem cell niche and provides a tolerizing phenotype to the microbiota exposed enterocytes. To challenge these hypotheses, I aim to elucidate the molecular mechanisms by which hypoxia inhibits interferon induction in intestinal epithelial cells. Furthermore, I will address the importance of low oxygen conditions in the intestinal tract in controlling viral infection and maintaining gut homeostasis. The outcome of our research could help to develop antiviral strategies based on manipulating the response of intestinal epithelial cells to hypoxia.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Steeve Boulant