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

Abstract

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.

Cell death offers exceptional cellular and molecular windows for pharmacological interventions in protozoan parasites

“…A recent study by Rathore et al involved the role of caspase-like VAD-FMK-binding proteases in TSN-(Tudor staphylococcal nuclease) homolog in P. falciparum and spliceosomal complex degradation causes apoptosislike cell death of Plasmodium under cellular stress [52]. It is also worth noting that in contrast to viable parasites, which stimulate the CD4+T-cell proliferation, the apoptotic-like Leishmania induces anti-inflammatory mediator production by hijacking the host cells´ autophagy machinery, likely to silence host phagocytes contributing to the survival of the overall population [53]. A small scale study by Ni Nyoman and Lüder reached different conclusions, finding the possession of ancient apoptosis-like cell death machinery by T. gondii and its ability to be targeted by chemotherapeutic agents, such as clindamycin [54].…”

“…The dynamic rearrangement of oral, somatic cilia, infraciliatures and several cellular organelles to be sequestered within autophagosome and delivered to the lysosome where degradation occurs are critical for the systematic progression of autophagy [92,93]. It has been demonstrated that apoptotic-like Leishmania/amstigote hijacks the macrophages´ autophagy machinery by dampening T-cell-mediated parasite elimination [53]. As such, apoptotic-like cell death in a single-cell eukaryotic parasite could benefit the survival of the overall population and could be amenable to therapeutic intervention ( Figure 9).…”

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

“…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). The molecular mechanism(s) involved in leishmania mediated regulation of host autophagy have begun to emerge.…”

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

“…45 A recent study demonstrates apoptotic-like parasites activate the macrophages' autophagy machinery, thereby dampening T-cell responses and enhancing parasite survival. 45 In the present study we found upregulation of host cell autophagy in response to Leishmania infection that appears to be a host protective response at 24 and 36 h. MIR30A-3p-dependent downregulation of autophagy at 48 h, ensured survival of intracellular Leishmania. Furthermore, anti-miR-mediated intervention resulted in significantly reduced parasite burden possibly by restoring the host-cell autophagic machinery.…”