Innate Immunity in the gut

Intestinal epithelial cells (IECs) lining the surface of our gut constitute the primary barrier that enteric pathogens have to face to establish infection.

 

IECs are polarized. They have an apical and a  basolateral plasma membrane that  display different lipids and proteins confering both membranes functional differences.

 

Although these cells are fully competent in recognizing and fighting pathogens they have developed unique mechanims to tolerate the presence of the commensal flora located in the lumen of our digestive tract. This ability to differentiate the "good" and the "bad" microbes is key to maintain epithelium homeostasis. Mis-regulation of this fine-tuned mechanisms leads to inflamatory bowel diseases (ie. IBD crohn etc...).

Schematic of polarized epithelial cells during viral infection. virus particles traffick into different endosomal compartments depending of entry side.

In the Boulant Lab, we are addressing how cellular polarity in IECs affects general processes involved in enteric virus infection. Particularly, we are addressing the role of cellular polarity on virus endocytosis, intracellular trafficking and virus recognition by pathogen recognition receptors (PRRs).

Reovirus infection of polarized intestinal epithelial cells

Reovirus infected IECs

Reovirus infected IECs

Reovirus infected mouse intestinal o

Reovirus infected mouse intestinal organoid

Endosomal trafficking of  reovirus

Endosomal trafficking of reovirus particles

We have determined that the two forms of mammalian reovirus (virions vs ISVPs) differently infect polarized intestinal epithelial cells. This differential infection leads to unique innate immunity and cell death profiles. We are currently characterizing these differences to better understand both the mechanisms by which enteric viruses infect IECs and the mechanisms by which IECs fight pathogens.

Cellular polarity and innate immunity

We are determining how cellular polarity and polarized endosomal trafficking impact sensing of viral infection by the innate immune system.

We beleive that the cellular polarity program in IECs not only controls the barrier funtion of this epithelium but also allows for the establishment of a tailored immune response fundamental for gut homeostasis and for the tolerance of the commensal apical (lumenal side) microbiota.

mouse intestinal organoids

mouse intestinal organoids

Mitochondria staining

Mitochondria in IECs

Tight junctions (Zo-1)

Tight junctions (Zo-1) in IECs

Type I vs. type III IFNs in epithelial cells

Stat phosphorylation

STAT signaling with type I and type III IFNs

VSV infected IECs

VSV infected IECs

IFN signalling pathway

IFN signalling pathway

Microarray after IFN treatment

Microarray after IFN treatment of IECS

Type I interferons have long been known to  play a critical role in anti-viral innate immunity. Type III interferons are a newly described class of immune factors. Interestingly, the type III interferon receptor is only expressed on mucosal surfaces, indicating a crucial role for them in these tissues. We are evaluating the similarities and differences between type I and III interferons in establishing and maintaining an anti-viral state in intestinal epithelial cells.

mouse intestinal organoids

mouse intestinal organoids