UPR triggered by leishmaniasis
Numerous studies have been done to assess the activated UPR in leishmaniasis caused by different Leishmania species, mainly,Leishmania braziliensis , Leishmania infantum, Leishmania donovani, and Leishmania amazonensis [1], [7], [47], [48].
The role of IRE1/XBP1-splicing arms of the UPR is well documented in viral and bacterial infections but poorly reported in protozoan parasitic infections. In an attempt to investigate the role of ER stress during Leishmania amazonensis infection, Dias-Teixeira et al . group demonstrated that, upon infection by Leishmania amazonensis , the IRE1-XBP1 branch of UPR gets activated to overcome the cellular oxidative stress and leads to up-regulation of IFN-1β which helps in establishment of infection and its pathogenesis [47]. Induction of IFN-1β expression in Leishmania amazonensisinfection is dependent on Toll-Like Receptor 2 (TLR2) activation, which is a pattern recognizing receptor and IFN-1β appears to favorLeishmania amazonensis parasite growth[49]. Further studies by this group have shown that ER-stress response enhancesLeishmania amazonensis infection in IFN-1 dependent manner.Leishmania amazonensis activates ER stress response by inducing the IRE1-XBP1 branch which subsequently leads to the splicing of XBP1 and nuclear translocation. By knocking down the expression of XBP1, they observed a reduction in infection mediated by the reduction of IFN-1β. Furthermore, down-regulation of heme oxygenase (HO) and an increase in cellular Nitric Oxide (NO) concentration were also reported when the XBP1 was knocked down. These experimental data collectively suggest that XBP1 is critical for Leishmania amazonensis growth in infected macrophages and the promotion of Leishmania amazonensis infection by XBP1 is dependent on IFN-1β[47]. With all the data available up to date, the study group has proposed a model which deciphers the role of XBP1 during Leishmania amazonensis infection as shown in figure 4 and 5.