In vivo and in vitro Leishmania amazonensis infection induces autophagy in macrophages

Cyrino, Larissa Tavares; Araújo, Alexandra Paiva; Joazeiro, Paulo Pinto; Vicente, Cristina Pontes; Giorgio, Selma

doi:10.1016/j.tice.2012.08.003

Cited by 56 publications

(70 citation statements)

References 38 publications

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“…Several species of leishmania have been observed to induce host autophagy, but the molecular mechanism(s) involved in the autophagy response have only recently begun to emerge (12)(13)(14)(15)(16)(17)(18)(19). For example, two recent studies reported a link between leishmania induced autophagy and a differentially expressed set of host micro RNAs (miRNAs), including MIR-30A-3p in infected cells (17,18).…”

Section: Discussionmentioning

confidence: 99%

“…Another study reported the accumulation of LC3-II in human bone marrow cells during L. donovani infection (13). Furthermore, induction of autophagy in infected macrophages has been linked to increased growth and parasite load of Leishmania amazonensis (14,15). Most recently, it has been found that Leishmania major uses macrophage autophagy to inhibit T-cell responses and prevent parasite clearance (16).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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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“…Indeed, autophagy is an important mechanism used by host immune cells to kill intracellular pathogens (e.g., Helicobacter pylori [51], Leishmania amazonensis [52], and Toxoplasma gondii [53]) or to provide some defense against intracellular pathogens (50). Furthermore, various bacteria and viruses regulate autophagy to avoid degradation through this pathway (54,55).…”

Section: Discussionmentioning

confidence: 99%

Microfilariae of Brugia malayi Inhibit the mTOR Pathway and Induce Autophagy in Human Dendritic Cells

et al. 2016

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Immune modulation is a hallmark of patent filarial infection, including suppression of antigen-presenting cell function and downmodulation of filarial antigen-specific T cell responses. The mammalian target of rapamycin (mTOR) signaling pathway has been implicated in immune regulation, not only by suppressing T cell responses but also by regulating autophagy (through mTOR sensing amino acid availability). Global proteomic analysis (liquid chromatography-tandem mass spectrometry) of microfilaria (mf)-exposed monocyte-derived dendritic cells (DC) indicated that multiple components of the mTOR signaling pathway, including mTOR, eIF4A, and eIF4E, are downregulated by mf, suggesting that mf target this pathway for immune modulation in DC. Utilizing Western blot analysis, we demonstrate that similar to rapamycin (a known mTOR inhibitor), mf downregulate the phosphorylation of mTOR and its regulatory proteins, p70S6K1 and 4E-BP1, a process essential for DC protein synthesis. As active mTOR signaling regulates autophagy, we examined whether mf exposure alters autophagy-associated processes. mf-induced autophagy was reflected in marked upregulation of phosphorylated Beclin 1, known to play an important role in both autophagosome formation and autolysosome fusion, in induction of LC3II, a marker of autophagosome formation, and in induced degradation of p62, a ubiquitin-binding protein that aggregates protein in autophagosomes and is degraded upon autophagy that was reduced significantly by mf exposure and by rapamycin. Together, these results suggest that Brugia malayi mf employ mechanisms of metabolic modulation in DC to influence the regulation of the host immune response by downregulating mTOR signaling, resulting in increased autophagy. Whether this is a result of the parasite-secreted rapamycin homolog is currently under study.

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“…Earlier reports indicate induction of autophagy in human and murine macrophages infected with different Leishmania species. 17,32,33 The regulatory role of MIR30 family members in downregulation of several genes (e.g., BECN1) involved in autophagy process in cancer cells and infection models has been reported earlier. [34][35][36] Figure 2.…”

Section: Introductionmentioning

confidence: 71%

MicroRNA expression profiling ofLeishmania donovani-infected host cells uncovers the regulatory role of MIR30A-3p in host autophagy

et al. 2016

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Leishmania is an obligate intracellular parasite that replicates inside phagolysosomes or parasitophorous vacuoles (PV) of the monocyte/macrophage lineage. It reprograms macrophages and produces a metabolic state conducive to successful infection and multiplication. MicroRNAs (miRNAs), a class of small 22 to 24 nucleotide noncoding regulatory RNAs alter the gene expression and consequently proteome output by targeting mRNAs, may play a regulatory role in modulating host cell functions. In the present study, we demonstrate the novel regulatory role of host microRNA, MIR30A-3p in modulation of host cell macroautophagy/autophagy after infection with L. donovani. Our in vitro studies showed that MIR30A-3p expression was significantly enhanced after L. donovani infection in a time-dependent manner. Transient transfection with a MIR30A-3p inhibitor followed by L. donovani infection promoted the autophagic response and decreased the intracellular parasite burden in both THP-1 cells and human monocytederived macrophages (HsMDM). BECN1/Beclin 1, the mammalian ortholog of yeast Vps30/Atg6, is a key autophagy-promoting protein that plays a key role in the regulation of cell death and survival. We report BECN1-dependent modulation of host cell autophagy in response to L. donovani infection. Pretreatment of L. donovani-infected macrophages with the MIR30A-3p mimic decreased and with antagomir increased the expression of BECN1 protein. We demonstrate that BECN1 is a potential target of MIR30A-3p and this miRNA negatively regulates BECN1 expression. Our present study reveals for the first time a novel role of MIR30A-3p in regulating autophagy-mediated L. donovani elimination by targeting BECN1. The present study has significant impact for the treatment of visceral leishmaniasis.

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In vivo and in vitro Leishmania amazonensis infection induces autophagy in macrophages

Cited by 56 publications

References 38 publications

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

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

Microfilariae of Brugia malayi Inhibit the mTOR Pathway and Induce Autophagy in Human Dendritic Cells

MicroRNA expression profiling ofLeishmania donovani-infected host cells uncovers the regulatory role of MIR30A-3p in host autophagy

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