PARylation can alter the function of proteins in several ways

atidylinositol anchored surface antigens can bind to TLR2 and/or TLR4; Plasmodium hemozoin can activate the inflammasome and TLR9; and Toxoplasma profilin binds to TLR11 and TLR12. These interactions, in turn, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19645759 trigger the production of proinflammatory cytokines, including IL-1, IL-6, TNF-a and IL-12. To this list, we can now add the induction of type I interferon responses via TLR3 and TRIF, and our in vitro data suggest that parasite RNA is a potential trigger for this response. Infection by protozoan parasites has typically been associated with induction of type II interferon, while type I interferon is prominent in viral infection, but type I responses to protozoa are not completely unprecedented. Toxoplasma infection elicits type I interferon from plasmacytoid dendritic cells, a cell type known to be a common source of this cytokine, while TLR3-Dependent Recognition of Protozoan Parasites splenic red pulp macrophages produce type I interferon when exposed to Plasmodium-infected erythrocytes. The parasite ligand was not identified in these studies, but the response was found to be Tlr11-dependent and Tlr9-/Myd88dependent. More recently, a type I interferon transcriptional signature has been noted in hepatocytes infected with live Plasmodium sporozoites, involving the cytosolic RNA sensor MDA5 and the MAVS adaptor protein. Although clearly distinct from the Tlr3- and Trif-dependent response to Neospora reported above, these observations support the concept that protozoan parasites can be robust activators of type I interferon signaling, and that mechanisms of innate sensing may vary depending on tissue or target cell type, parasite developmental stage, or other factors. Although we found that both parasite species are capable of activating type I interferon responses when killed and added to cells directly, the level of induction was a log order of magnitude higher with Neospora. This may explain why transfection of macrophages with Neospora RNA, but not Toxoplasma RNA, was sufficient to elicit a TLR3-dependent induction of type I interferon responsive genes. These findings suggest that there are quantitative and/or qualitative differences in TLR3 ligand present in RNA from these parasite species. Both Toxoplasma and Neospora establish an intracellular `parasitophorous vacuole’ distinct from the endo-lysosomal pathway at the time of invasion, raising the question of how parasite antigens, including nucleic acids, gain MedChemExpress Neuromedin N access to endosomal TLR3 or other intracellular pattern recognition receptors. One possibility is that TLR3 activation may be attributable to the release of RNA from parasites that are 6 TLR3-Dependent Recognition of Protozoan Parasites phagocytosed or that die after invasion, rather than those engaged in productive intracellular replication. Alternatively, since the PV is intimately associated with the host mitochondria and endoplasmic reticulum, it is possible that RNA within the PV may access the host endo-lysosomal system. PV antigens are known to enter the host endoplasmic reticulum for processing and presentation to T cells on MHC class I. Endosomal vesicles may also be recruited to the PV, facilitating the acquisition of nutrients, and perhaps playing a role in escape from the host cell. While type I and II interferons utilize different receptors and transcription factors, there is significant overlap in the genes that they induce, suggesting some degree of functional redundancy. We observed that Neospora infectio