PI3K signaling in Leishmania infections

Kima, Peter E.

doi:10.1016/j.cellimm.2016.09.004

Cited by 12 publications

(17 citation statements)

References 24 publications

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“…In this study, the phosphorylation of PI3K/AKT was found to be increased in L. donovani infected macrophages when compared to noninfected macrophages. Our findings demonstrated that Leishmania infection induces PI3K/AKT pathway which was agreement with the previous reports by Ruhland et al ( 68 ) and Kima et al ( 69 ). The involvement of LdISP2 in C5aR-mediated signaling was evaluated by measuring the phosphorylation status of p-AKT and p-PI3K during macrophage infection with ISP2KD and ISP2OE parasites.…”

Section: Discussionsupporting

confidence: 94%

Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host

et al. 2018

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Leishmania donovani, the causative agent of Indian visceral leishmaniasis has to face several barriers of the immune system inside the mammalian host for its survival. The complement system is one of the first barriers and consists of a well-balanced network of proteases including S1A family serine proteases (SPs). Inhibitor of serine peptidases (ISPs) is considered as inhibitor of S1A family serine peptidases and is reported to be present in trypanosomes, including Leishmania. In our previous study, we have deciphered the role of ISPs [LdISP1 and L. donovani inhibitor of serine peptidases 2 (LdISP2)] in the survival of L. donovani inside the sandfly midgut. However, the role of theses ISPs in the survival of L. donovani inside mammalian host still remains elusive. In the present study, we have deciphered the inhibitory effect of LdISPs on the host complement S1A serine peptidases, such as C1r/C1s and MASP1/MASP2. Our study suggested that although both rLdISP1 and rLdISP2 inferred strong interaction with C1complex and MBL-associated serine proteases (MASPs) but rLdISP2 showed the stronger inhibitory effect on MASP2 than rLdISP1. Moreover, we found that rLdISP2 significantly reduces the formation of C3, C5 convertase, and membrane attacking complex (MAC) by lectin pathway (LP) resulting in significant reduction in serum mediated lysis of the parasites. The role of LdISP2 on neutrophil elastase-mediated C5aR signaling was also evaluated. Notably, our results showed that infection of macrophages with ISP2-overexpressed Leishmania parasites significantly induces the expression of C5aR both at the transcript and translational level. Simultaneously, infection with ISP2KD parasites results in downregulation of host PI3K/AKT phosphorylation and increased in IL-12 production. Taken together, our findings clearly suggest that LdISP2 promotes parasite survival inside host by inhibiting MAC formation and complement-mediated lysis via LP and by upregulation of C5aR signaling.

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Section: Discussionsupporting

confidence: 94%

Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host

et al. 2018

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“…In this context, it is known that leishmania confers host cell resistance to apoptosis by activating Akt (28,66). Third, activation of mTOR-independent autophagy, in the background of sustained activation of PI3K-Akt pathway would allow for fine tuning of autophagy for optimal acquisition of essential nutrients from the host.…”

Section: Discussionmentioning

confidence: 99%

Countervailing, time-dependent effects on host autophagy promote intracellular survival of Leishmania

Thomas

Nandan

Kass

et al. 2018

Journal of Biological Chemistry

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Autophagy is essential for cell survival under stress and implicated in host defence. Here, we investigated the interactions between Leishmania donovani, the main etiological agent of visceral leishmaniasis, and the autophagic machinery of human macrophages. Our results revealed that during early infection-and via activation of the Akt pathway-leishmania actively inhibits the induction of autophagy. However, by 24 h, leishmania switched from being an inhibitor to an overall inducer of autophagy. These findings of a dynamic, biphasic response were based on the accumulation of lipidated light chain 3 (LC3), an autophagosome marker, by Western blotting and confocal fluorescence microscopy. We also present evidence that leishmania induces delayed host cell autophagy via a mechanism independent of reduced activity of mechanistic target of rapamycin (mTOR). Notably, leishmania actively inhibited mTOR-regulated autophagy even at later stages of infection, while there was a clear induction of autophagy via some other mechanism. In this context, we examined host inositol monophosphatase (IMPase), reduced levels of which have been implicated in mTORindependent autophagy, and found that IMPase activity is significantly decreased in infected cells. These findings indicate that leishmania uses an alternative pathway to mTOR to induce autophagy in host macrophages. Lastly, RNAi-mediated downregulation of host autophagy protein 5 (ATG5) or autophagy protein 9A (ATG9A) decreased parasite loads, demonstrating that autophagy is essential for leishmania survival. We conclude that leishmania uses an alternative pathway to induce host autophagy while simultaneously inhibiting mTOR-regulated autophagy to fine-tune the timing and magnitude of this process and optimize parasite survival.http://www.jbc.org/cgi

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“…Several studies had observed that the PI3K/Akt signalling pathway is activated in Leishmania infections and that inhibition of this pathway has a negative impact on the course of Leishmania infections (reviewed by Kima, ). In the current studies, we evaluated tetracycline inducible Akt1 shRNA cell lines that could be induced to knockdown Akt1 levels.…”

Section: Discussionmentioning

confidence: 99%

“…The biogenesis and composition of LPVs are not fully understood. Internalisation of Leishmania parasites engages phosphatidyl‐inositol 3‐kinase (PI3K) signalling, which plays an important role in the infection (Kima, ). Activation of PI3K signalling in cells is initiated by PI3K enzymes at the site of hormone or phagocytic receptor engagement in the plasma membrane (PM).…”

Section: Introductionmentioning

confidence: 99%

Leishmaniaparasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine inLeishmaniainfections

Zhang

Prasad

Despointes

et al. 2018

Cellular Microbiology

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Miltefosine is an important drug for the treatment of leishmaniasis; however, its mechanism of action is still poorly understood. In these studies, we tested the hypothesis that like in cancer cells, miltefosine's efficacy in leishmaniasis is due to its inhibition of Akt activation in host cells. We show using pharmacologic agents that block Akt activation by different mechanisms and also using an inducible knockdown approach that miltefosine loses its efficacy when its access to Akt1 is limited. Interestingly, limitation of Akt activation results in clearance of established Leishmania infections. We then show, using fluorophore-tagged probes that bind to phosphoinositides, that Leishmania parasitophorous vacuole membranes (LPVMs) display the relevant phosphoinositides to which Akt can be recruited and activated continuously. Taken together, we propose that the acquisition of PI(4) P and the display of PI (3,4)P2 on LPVMs initiate the machinery that supports continuous Akt activation and sensitivity to miltefosine.

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PI3K signaling in Leishmania infections

Cited by 12 publications

References 24 publications

Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host

Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host

Countervailing, time-dependent effects on host autophagy promote intracellular survival of Leishmania

Leishmaniaparasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine inLeishmaniainfections

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