Authors

MP Clark¹; L Mackiewicz¹; M Doerflinger¹; M Pellegrini¹;  ¹ The Walter and Elisa Hall Institute, Australia

Discussion

Leishmaniasis, a disease caused by the Leishmania spp. parasite, affects approximately 1 million people annually worldwide. Specific Leishmania species such as Leishmania donovani cause chronic spleen, liver and bone marrow infection which if left untreated leads to a fatal visceral infection resulting in 20,000-30,000 deaths globally each year. The rise of resistance among many of the current therapeutics for visceral leishmaniasis and the severe toxicity profiles of these anti-leishmanials suggest there is a desperate need for new, safer therapeutics for the treatment of leishmaniasis.  Re-purposing already established therapeutics that target the host are an attractive target as they can be more rapidly deployed clinically than completely novel compounds and are less likely to elicit a selective pressure for resistance in the parasite as successful evasion would require considerable mutational changes.

As intracellular pathogens such as Leishmania spp. need to manipulate host cell death signaling pathways to survive, replicate and disseminate, we hypothesise that therapeutics originally designed for the treatment of various cancers that target these cell death pathways may provide effective new treatments for visceral leishmaniasis.

We used L. donovani in vitro and in vivo infection models along with microscopy, live-cell imaging, ELISAs, flow cytometry and immunohistochemistry to determine the effectiveness of therapeutic compounds targeting host cell apoptotic machinery for the treatment of visceral leishmaniasis.

Our results explored the impact of therapeutically inducing extrinsic apoptosis in Leishmania donovani infection. We showed that tumour necrosis factor (TNF), the instigator of extrinsic apoptosis, is upregulated in Leishmania donovani infection, however only upon the addition of inhibitor of apoptosis proteins (IAPs) inhibitors does cell death of infected cells occur. Infected mice treated with IAP inhibitors showed a decrease in parasite burden as well as a corresponding decrease in hepatosplenomegaly. More importantly, there is an additive effect when this therapeutic is combined with anti-leishmanial amphotericin-B, indicating IAP inhibitors could be used to enhance amphotericin-B therapy or enable the reduction of standard amphotericin-B dosage to decrease toxicity. 

Collectively, these data showed that targeting host extrinsic apoptotic pathways using clinical stage IAP inhibitors may be a valid therapeutic option for the treatment of visceral leishmaniasis.