Pathogens teach us about novel antiinflammatory strategies – PATHIMMUN

Our project is based upon the original concept that bacterial pathogens, under strong selective pressure in order to avoid the inflammatory immune reactions of their infected host and to achieve efficient colonization and invasion, have accumulated, during their long co-evolution with higher primates, a variety of genes encoding very efficient « anti-immunity » mechanisms. Enteroinvasive bacterial pathogens such as Shigella, Salmonella and Yersinia which recapitulate all possible steps of interaction (i.e. intracellular, extracellular) with the intestinal epithelium, and resident/recruited immune cells of the lamina propria, harbor a rich array of “anti-immunity” effectors that are injected into the target cell cytoplasm via a dedicated type III secretory apparatus (TTSS). Altogether these effectors represent a “gold mine” of strategies - thus of ideas - to manipulate and control the arms of the immune system that cooperate to eradicate invading microorganisms. Whether innate or adaptive, host immune mechanisms converge in eliciting cells (i.e. monocytes, dendritic cells, Th1 and Th17 T-lymphocytes) producing high amounts of pro-inflammatory cytokines and chemokines that recruit and activate phagocytes at the cost of massive tissue damage. For pathogens, survival indeed requires that they can inactivate key signaling cascades of this inflammatory reaction both in epithelial and immune cells. The ongoing molecular and cellular analysis of the mode of action of these “anti-immunity” effectors reveals that they are in general enzymes able to carry out modifications of original functions of host proteins that represent – or belong to – check points in pro-inflammatory cascades (i.e. I-?B, IKK, ERK/P38, etc…). Enzymatic activities vary from ubiquitin ligases to deubiquitinases, kinases to phosphatases or phosphothreonine lyases, methylases, etc… It appears that this variety of enzymes is largely dedicated to the dampening of the NF-?B and MAPKinases pathways, than one may consider “expected” therefore less prone to provide original targets for the development of novel anti-inflammatory drugs.
Based on this rational, we decided to select another TTSS-injected effector, IpgD, that stands out as a phosphatidylinositol phosphatase hydrolyzing PI(4,5)P2 in PI5P. We have recently shown that in experimental models of Shigella infection, IpgD is the effector that expresses the strongest anti-inflammatory effect. Our preliminary evidence indicate that through the loss of PI(4,5)P2, or rather the acquisition of the largely unknown PI5P, IpgD interferes very efficiently with various cellular mechanisms that altogether contribute to strong “anti-immunity” functions, particularly anti-inflammatory. Altered mechanisms may be provisionally classified into three categories which will support the four lines of our project: (i) the regulation of danger signals by hemichannel closing that regulates the pro-inflammatory release of ATP induced by invaded epithelial cells; (ii) the efficient control of Ca2+ fluxes induced by bacterial invasion signals, inhibition of these fluxes participating in the regulation of hemichannel opening; (iii) the regulation of EGF receptor activation and recycling whose function may not be essential to regulate inflammation, but will serve as a blue print to study how IpgD affects the function and surface exposure of key immune receptors; (iv) the control of immune cell migration via modifications of the dynamics of the cytoskeleton of immune cells.
From this very basic dissection of the anti-inflammatory mode of action of IpgD, we wish to identify possible original targets for novel anti-inflammatory strategies, and to develop robust dedicated readouts that we will ultimately propose to interested company partners to identify new type/families of anti-inflammatory drugs. We will actively seek industrial partnership in the course of this project.