Obtaining extra precise information regarding the relative relevance of CagA?s interactions with host cell proteins will require investigation of their downstream results on intact epithelial tissue. To be able to examine the effects of each bacterial and host genetic things, our group has formulated a method by which Drosophila melanogaster is employed to model pathogenesis of your H. pylori virulence factor CagA . There are numerous properties that make this model organism very well suited for studying the pathogenic effects of CagA expression. Primary, quite a few canonical cell signaling pathways are extensively characterized in Drosophila and present large conservation together with the homologous pathways in people. Also, genetic resources just like the GAL4 UAS system permit expression of CagA in certain cells inside an epithelium and examination of how CagA expressing cells interact with neighboring wild form cells.
Last but not least, we are able to easily manipulate host genes employing resources created from the wealthy Drosophila research neighborhood to assess likely results on CagA induced phenotypes. In addition, our model makes it possible for us to check no matter if CagA?s interactions are phosphorylation dependent via expression of the mutant form of CagA recognized Ridaforolimus as CagAEPISA, through which the EPIYA phosphorylation motifs have already been deleted or mutated . Utilization of this model has presently offered insight into CagA?s role in manipulating receptor tyrosine kinases, the Rho signaling pathway and epithelial junctions . Epithelial polarity is a single necessary characteristic of host cells regarded to get perturbed by CagA. Strains of H. pylori that encode CagA are exclusively ready to trigger localized disruption of apicobasal polarity in order to colonize a polarized monolayer of tissue culture cells . CagA positive strains of H.
pylori have also been shown to lead to apoptosis in the two cultured gastric cancer cells and human gastric biopsies , even though the role of CagA dependent apoptosis in H. pylori pathogenesis remains controversial. Reduction of epithelial cell polarity is shown to induce apoptotic cell death or promote tumorigenesis in numerous selleckchem MS-275 cellular and genetic contexts . Cell death resulting from polarity disruption can trigger compensatory proliferation as a way to change lost cells, but this practice can become tumorigenic in the presence of genetic alterations that block apoptosis . This mechanism has been proposed to explain how the potential of CagA to disrupt cell polarity and induce apoptosis may perhaps be linked to its tumorigenic probable, but the host cell signaling pathways that might mediate these downstream results haven’t been identified .
An important host signaling pathway that triggers apoptosis downstream of cell polarity disruption stands out as the c Jun NH2 terminal kinase pathway. JNK can be a strain activated protein kinase with a lot of upstream activators such as cytokines, mitogens, osmotic worry, ultraviolet radiation and reduction of cell polarity .