Lipase precursor like protein promotes miltefosine tolerance in Leishmania donovani by enhancing parasite infectivity and eliciting anti-inflammatory responses in host macrophages [Mechanisms of Resistance]

Oral drug miltefosine (MIL) was introduced in the Indian subcontinent in the year 2002 for the treatment of visceral leishmaniasis (VL). However, recent reports on its declining efficacy and increasing relapse rates pose a serious concern. An understanding of the factors contributing to MIL tolerance in Leishmania parasites is critical. In the present study, we assessed the role of lipase precursor like protein (Lip) in conferring tolerance towards miltefosine by episomally overexpressing Lip into L. donovani (LdLip⁺⁺). We observed significant increase (~3 fold) in MIL IC₅₀ both at promastigote (3.90 ± 0.68 µM, P<0.05) and at intracellular amastigote (9.10 ± 0.60 µM, P<0.05) stages compared to the wild type counterpart (LdNeo; MIL IC₅₀ promastigote 1.49 ± 0.20 µM; MIL IC₅₀ amastigote 3.95 ± 0.45 µM). LdLip⁺⁺ parasites exhibited significantly (P<0.05) increased infectivity to host macrophages, increased metacyclogenesis and tolerance to MIL induced oxidative stress. The susceptibility of LdLip⁺⁺ towards other antileishmanial drugs (sodium antimony gluconate and amphotericin B) remained unchanged. In comparison to LdNeo, the LdLip⁺⁺ parasites elicited higher host IL-10 cytokine expression (1.6 fold, P<0.05) with reduced expression of TNF-α cytokine (1.5 fold, P<0.05), leading to significantly (P<0.01) increased ratio of IL-10/TNF- α. The above findings suggest a role of lipase precursor like protein in conferring tolerance towards oral antileishmanial drug MIL in L. donovani parasites.

https://ift.tt/2PlziQN