Leishmania Evades Host Immunity by Inhibiting Antigen Cross-Presentation through Direct Cleavage of the SNARE VAMP8

Matheoud, Diana; Moradin, Neda; Bellemare-Pelletier, Angélique; Shio, Marina Tiemi; Hong, Wan Jin; Olivier, Martin; Gagnon, Étienne; Desjardins, Michel; Descoteaux, Albert

doi:10.1016/j.chom.2013.06.003

Cited by 124 publications

(192 citation statements)

References 54 publications

(75 reference statements)

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“…42 A recent study in mice using L. donovani demonstrated a reduced T-cell proliferation caused by the inhibition of Leishmania antigens cross-presented on MHC class I molecules. 43 In agreement with these data we could observe Leishmania major parasites to indirectly reduce T-cell proliferation and this inhibitory effect was depending on the presence of apoptotic-like Leishmania parasites.…”

Section: Discussionsupporting

confidence: 78%

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: Discussionsupporting

confidence: 78%

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

et al. 2015

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“…Previous studies have supported this hypothesis (8). Among parasitic proteases, metalloproteases have been related to pathogenesis and are involved in processes such as immunity evasion, development, and metabolism (9)(10)(11). Analysis of the E. tenella genome revealed the presence of at least 45 proteases, 31% of which were metalloproteases, that are transcribed in different stages of the parasite life cycle (12).…”

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confidence: 68%

Aminopeptidase N1 (EtAPN1), an M1 Metalloprotease of the Apicomplexan Parasite Eimeria tenella, Participates in Parasite Development

et al. 2014

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Aminopeptidases N are metalloproteases of the M1 family that have been reported in numerous apicomplexan parasites, including Plasmodium, Toxoplasma, Cryptosporidium, and Eimeria. While investigating the potency of aminopeptidases as therapeutic targets against coccidiosis, one of the most important avian diseases caused by the genus Eimeria, we identified and characterized Eimeria tenella aminopeptidase N1 (EtAPN1). Its inhibition by bestatin and amastatin, as well as its reactivation by divalent ions, is typical of zinc-dependent metalloproteases. EtAPN1 shared a similar sequence, three-dimensional structure, and substrate specificity and similar kinetic parameters with A-M1 from Plasmodium falciparum (PfA-M1), a validated target in the treatment of malaria. EtAPN1 is synthesized as a 120-kDa precursor and cleaved into 96-, 68-, and 38-kDa forms during sporulation. Further, immunolocalization assays revealed that, similar to PfA-M1, EtAPN1 is present during the intracellular life cycle stages in both the parasite cytoplasm and the parasite nucleus. The present results support the hypothesis of a conserved role between the two aminopeptidases, and we suggest that EtAPN1 might be a valuable target for anticoccidiosis drugs.

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“…Interestingly, the sporoplasm release was prevented by 1,10-phenanthroline (metalloprotease) and it suggested that metalloprotease is related the sporoplasm release in K. septempunctata [26]. Metalloproteases of parasite have been related to pathogenesis and are involved in processes such as immunity evasion, development, and metabolism [8,17]. In addition, the activity of metalloproteases are affected by pH of environment [13].…”

Section: Discussionmentioning

confidence: 99%

Characterization of proteases isolated from Kudoa septempunctata

Shin¹,

Zenke²,

Yokoyama³

2015

Korean Journal of Veterinary Research

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: Proteases play important roles in parasite development and host parasite interactions. The protease of Kudoa spp. has been recognized as a key factor of severe proteolysis of fish muscle post-mortem; however, there is little information available regarding the protease of Kudoa (K.) septempunctata, which was recently identified as a cause of food poisoning in humans. The present study was conducted to isolate and characterize proteases to elucidate the type of protease contained in the parasite and determine the optimal pH for protease activity. We confirmed the cysteine protease and metalloprotease produced by K. septempunctata. While the cysteine protease showed optimal activity at pH 5 that decreased rapidly with increasing pH, the optimal activity of metalloprotease was pH 7, and it remained stable from pH 6 to pH 8. These results indicate that the pH of cysteine protease is not proper for fish muscle postmortem, and that metalloprotease can act in human intestines. Overall, the present study provides important information that improves our understanding of the role of protease physiology and the subsequent food poisoning caused by K. septempunctata.

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Leishmania Evades Host Immunity by Inhibiting Antigen Cross-Presentation through Direct Cleavage of the SNARE VAMP8

Cited by 124 publications

References 54 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

Aminopeptidase N1 (EtAPN1), an M1 Metalloprotease of the Apicomplexan Parasite Eimeria tenella, Participates in Parasite Development

Characterization of proteases isolated from Kudoa septempunctata

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