The 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 the
lipase precursor-like
protein (Lip) in conferring tolerance to
miltefosine by episomally overexpressing Lip in Leishmania donovani (LdLip++). We observed a significant increase (∼3-fold) in the
MIL 50% inhibitory concentration (IC50) at both the promastigote (3.90 ± 0.68 µM; P < 0.05) and intracellular amastigote (9.10 ± 0.60 µM; P < 0.05) stages compared to the wild-type counterpart (LdNeo) (
MIL IC50s of 1.49 ± 0.20 µM at the promastigote stage and 3.95 ± 0.45 µM at the amastigote stage). LdLip++ parasites exhibited significantly (P < 0.05) increased infectivity to host macrophages and increased metacyclogenesis and tolerance to
MIL-induced oxidative stress. The susceptibility of LdLip++ to other antileishmanial drugs (
sodium antimony gluconate and
amphotericin B) remained unchanged. In comparison to LdNeo, the LdLip++ parasites elicited high host
interleukin-10 (IL-10)
cytokine expression levels (1.6-fold; P < 0.05) with reduced expression of the
cytokine tumor necrosis factor alpha (TNF-α) (1.5-fold; P < 0.05), leading to a significantly (P < 0.01) increased ratio of IL-10/TNF-α. The above-described findings suggest a role of
lipase precursor-like
protein in conferring tolerance to the oral antileishmanial drug
MIL in L. donovani parasites.