Abstract
The heat shock protein 90 (Hsp90) is thought to be an excellent drug target against parasitic diseases. The leishmanicidal effect of an Hsp90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), was previously demonstrated in both in vitro and in vivo models of cutaneous leishmaniasis. Parasite death was shown to occur in association with severe ultrastructural alterations in Leishmania, suggestive of autophagic activation. We hypothesized that 17-AAG treatment results in the abnormal activation of the autophagic pathway, leading to parasite death. To elucidate this process, experiments were performed using transgenic parasites with GFP-ATG8-labelled autophagosomes. Mutant parasites treated with 17-AAG exhibited autophagosomes that did not entrap cargo, such as glycosomes, or fuse with lysosomes. ATG5-knockout (Δatg5) parasites, which are incapable of forming autophagosomes, demonstrated lower sensitivity to 17-AAG-induced cell death when compared to wild-type (WT) Leishmania, further supporting the role of autophagy in 17-AAG-induced cell death. In addition, Hsp90 inhibition resulted in greater accumulation of ubiquitylated proteins in both WT- and Δatg5-treated parasites compared to controls, in the absence of proteasome overload. In conjunction with previously described ultrastructural alterations, herein we present evidence that treatment with 17-AAG causes abnormal activation of the autophagic pathway, resulting in the formation of immature autophagosomes and, consequently, incidental parasite death.
Highlights
Leishmania spp. are protozoan parasites [1,2] that cause leishmaniasis, which can present in a variety of clinical manifestations, including skin and visceral forms [3]
Treatment, we hypothesized that autophagic activation could be consequent to heat shock protein 90 (Hsp90) inhibition, which causes a subsequent enhancement in the amount of ubiquitylated protein
The present study confirmed that in Leishmania treated with 17-AAG, autophagy is induced by an increased percentage of autophagosomes expressing GFP-ATG8, as well as higher overall numbers of labeled autophagosomes per parasite
Summary
Leishmania spp. are protozoan parasites [1,2] that cause leishmaniasis, which can present in a variety of clinical manifestations, including skin and visceral forms [3]. Being one of the most important neglected tropical diseases, leishmaniasis affects millions of people worldwide. Financial investment in new therapeutic strategies has been scarce [3], resulting in pentavalent antimonials being the drug of choice for more than 70 years in Brazil. Antimonial therapy requires parenteral administration at high dosage and involves a lengthy therapeutic course that can result in a range of serious side effects [4]. Recent increases in therapeutic failure [5,6,7] reinforce the importance of developing new drugs capable of replacing or complementing existing strategies for leishmaniasis treatment. Recent increases in therapeutic failure [5,6,7] reinforce the importance of developing new drugs capable of replacing or complementing existing strategies for leishmaniasis treatment. 4.0/).
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