Induction of autophagy correlates with increased parasite load of Leishmania amazonensis in BALB/c but not C57BL/6 macrophages

Pinheiro, Roberta Olmo; Nunes, Marise P.; Pinheiro, Carla S.; D’Avila, Heloísa; Bozza, Patrı́cia T.; Takiya, Christina Maeda; Cortê-Real, Suzana; Freire-de-Lima, Célio Geraldo; DosReis, George A.

doi:10.1016/j.micinf.2008.11.006

Cited by 89 publications

(126 citation statements)

References 28 publications

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“…56 In addition, Roberta O. Pinheiro et al have found that autophagy increases the parasitic replication of Leishmania amazonensis inside macrophages. 23 In contrast, our data did not indicate autophagy to influence replication. However our data suggest that an elevated autophagy activity prevents the elimination of promastigotes.…”

Section: Discussioncontrasting

confidence: 95%

“…52 As described, autophagy is a key player in maintaining homeostasis, enabling phagocytes to clear apoptotic and necrotic cells efficiently and silently to prevent inflammation and development of autoimmune disorders, like systemic lupus erythematous. 23 Also in the presence of apoptotic parasites, immune responses were dampened, as infected hMDM induced a lower T-cell proliferation. Clearance of dying cells or even apoptotic-like Lm is known to create a more anti-inflammatory environment that is dominated by cytokines such as IL10 and TGFB and suppression of TNF, IL6 and IL1B.…”

Section: Discussionmentioning

confidence: 99%

“…21,22 Moreover, induction of autophagy correlates with an increased Leishmania parasite load. 23 Focusing on the latter one, we could already show that the virulent Leishmania inoculum consists partially of apoptotic-like parasites, through which disease development can occur. 1 In the present study we first characterized the apoptotic population and then determined the fate of apoptoticlike Leishmania parasites in human host macrophages and its significance for T-cell activation.…”

Section: Introductionmentioning

confidence: 97%

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Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

et al. 2015

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Apoptosis is a well-defined cellular process in which a cell dies, characterized by cell shrinkage and DNA fragmentation. In parasites like Leishmania, the process of apoptosis-like cell death has been described. Moreover upon infection, the apoptotic-like population is essential for disease development, in part by silencing host phagocytes. Nevertheless, the exact mechanism of how apoptosis in unicellular organisms may support infectivity remains unclear. Therefore we investigated the fate of apoptotic-like Leishmania parasites in human host macrophages. Our data showed-in contrast to viable parasites-that apoptotic-like parasites enter an LC3 C , autophagy-like compartment. The compartment was found to consist of a single lipid bilayer, typical for LC3-associated phagocytosis (LAP). As LAP can provoke anti-inflammatory responses and autophagy modulates antigen presentation, we analyzed how the presence of apoptotic-like parasites affected the adaptive immune response. Macrophages infected with viable Leishmania induced proliferation of CD4 C T-cells, leading to a reduced intracellular parasite survival. Remarkably, the presence of apoptotic-like parasites in the inoculum significantly reduced T-cell proliferation. Chemical induction of autophagy in human monocyte-derived macrophage (hMDM), infected with viable parasites only, had an even stronger proliferationreducing effect, indicating that host cell autophagy and not parasite viability limits the T-cell response and enhances parasite survival. Concluding, our data suggest that apoptotic-like Leishmania hijack the host cells´autophagy machinery to reduce T-cell proliferation. Furthermore, the overall population survival is guaranteed, explaining the benefit of apoptosis-like cell death in a single-celled parasite and defining the host autophagy pathway as a potential therapeutic target in treating Leishmaniasis.

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Section: Discussioncontrasting

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

et al. 2015

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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: 67%

“…15 Induction of host cell autophagy mediated by either starvation or cytokines alters the intracellular burden of Leishmania depending upon the strain of mice used in the study. 16,17 Depending on the cellular context, autophagy can either increase nutrient supply to starved cells via recycling of products or can act like a central antimicrobial defense complementing the innate immunity by restricting the growth and proliferation of invading pathogens. 18,19 The formation of autophagosomes is mediated by a series of autophagy-related gene products such as multiple autophagyrelated (ATG) proteins, several of which are associated into protein complexes controlling different stages of autophagy, including initiation and elongation of the phagophore, the precursor to the autophagosome.…”

Section: Introductionmentioning

confidence: 99%

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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Autophagy as an innate immunity response against pathogens: a Tango dance

Aguilera,

Delgui,

Reggiori

et al. 2023

FEBS Letters

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Intracellular infections as well as changes in the cell nutritional environment are main events that trigger cellular stress responses. One crucial cell response to stress conditions is autophagy. During the last 30 years, several scenarios involving autophagy induction or inhibition over the course of an intracellular invasion by pathogens have been uncovered. In this review, we will present how this knowledge was gained by studying different microorganisms. We intend to discuss how the cell, via autophagy, tries to repel these attacks with the objective of destroying the intruder, but also how some pathogens have developed strategies to subvert this. These two fates can be compared with a Tango, a dance originated in Buenos Aires, Argentina, in which the partner dancers are in close connection. One of them is the leader, embracing and involving the partner, but the follower may respond escaping from the leader. This joint dance is indeed highly synchronized and controlled, perfectly reflecting the interaction between autophagy and microorganism.

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Induction of autophagy correlates with increased parasite load of Leishmania amazonensis in BALB/c but not C57BL/6 macrophages

Cited by 89 publications

References 28 publications

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

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

Autophagy as an innate immunity response against pathogens: a Tango dance

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