Leishmania donovani induced Unfolded Protein Response delays host cell apoptosis in PERK dependent manner

Abstract

BackgroundEndoplasmic reticulum (ER) stress generated unfolded stress response (UPR) is a basic survival mechanism which protects cell under unfavourable conditions. Leishmania parasite modulates host macrophages in various ways to ensure its survival. Modulation of PI3K-Akt pathway in delayed apoptotic induction of host; enables parasite to stabilize the infection for further propagation.MethodologyInfected RAW macrophages were exposed to campothecin or thagsigargin and phosphorylation status of PERK, Akt, BAD and Cyt-C was determined through western blotting using phospho specific antibody. Expression at transcriptional level for cIAP1 &2, ATF4, CHOP, ATF3, HO-1 and sXBP1 was determined using real time PCR. For inhibition studies, RAW macrophages were pre-treated with PERK inhibitor GSK2606414 before infection.FindingsOur studies in RAW macrophages showed that induction of host UPR against L.donovani infection activates Akt mediated pathway which delays apoptotic induction of the host. Moreover, Leishmania infection results in phosphorylation and activation of host PERK enzyme and increased transcription of genes of inhibitor of apoptosis gene family (cIAP) mRNA. In our inhibition studies, we found that inhibition of infection induced PERK phosphorylation under apoptotic inducers reduces the Akt phosphorylation and fails to activate further downstream molecules involved in protection against apoptosis. Also, inhibition of PERK phosphorylation under oxidative exposure leads to increased Nitric Oxide production. Simultaneously, decreased transcription of cIAP mRNA upon PERK phosphorylation fates the host cell towards apoptosis hence decreased infection rate.ConclusionOverall the findings from the study suggests that Leishmania modulated host UPR and PERK phosphorylation delays apoptotic induction in host macrophage, hence supports parasite invasion at early stages of infection.

Trypanosomatid selenophosphate synthetase structure, function and interaction with selenocysteine lyase

“…donovani was also observed by Koumandou et al [ 71 ], Izquierdo et al [ 72 ], Tiengwe et al [ 32 ] and Abhishek et al [ 73 ], arguing that a UPR-like response based on BiP is inactive in trypanosomatids. On the other hand, these parasites also conserve PKR-like endoplasmic reticulum kinase (PERK) [ 73 ], a protein that regulates protein translation by phosphorylating eIF2a, in another mechanism of UPR response in mammals [ 74 ]. It is not expected that BSF T .…”

Parkin-Dependent Mitophagy is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats

“…ATF4, one of the major ERS (Endoplasmic Reticulum Stress) response effectors, is involved in a variety of diseases and its role in cell survival and death is not completely clear [37]. Upon severe or prolonged ER stress, activation of the PERK-elF2α-ATF4-CHOP signaling cascade is responsible for ER stress-induced apoptotic cell death as reported by several studies [38,39]. In contrast, other studies showed a pro-survival function of ATF4.…”

Leishmanicidal Potential of Hardwickiic Acid Isolated From Croton sylvaticus

“…HA was also predicted to possess antiprotozoal activity (specifically, antileishmanial) with Pa of 0.434 and Pi 0.037. From recent studies, Leishmania infections have been reported to delay host cell apoptosis by inhibiting caspase-3 activity (Ruhland et al, 2007;Abhishek et al, 2018). Caspase-8 inhibition following L. major infection has also been shown to decrease the expression of interferon gamma by CD4 and CD8 T cells (Pereira et al, 2008).…”