Label-Free Mass Spectrometry Proteomics Reveals Different Pathways Modulated in THP‑1 Cells Infected with Therapeutic Failure and Drug Resistance Leishmania infantum Clinical Isolates

As the world is facing
increasing difficulties to treat leishmaniasis
with current therapies, deeper investigation into the molecular mechanisms
responsible for both drug resistance and treatment failure (TF) is
essential in drug discovery and development. So far, few available
drugs cause severe side effects and have developed several resistance
mechanisms. Drug resistance and TF parasite strains from clinical
isolates may have acquired altered expression of proteins that characterize
specific mechanisms leading to therapy inefficacy. This work aims
to identify the biochemical pathways of THP-1 human monocytes infected
by different Leishmania infantum clinical
isolates from patients with either resistance or with TF outcome,
using whole cell differential Mass Spectrometry proteomics. We have
adopted network enrichment analysis to integrate the transcriptomics
and the proteomic results of infected cells studies. Transferrin receptor
C (TFRC) and nucleoside diphosphate kinase 3 (NDK3) were discovered
as overexpressed proteins in THP-1 cells infected with paromomycin,
antimony, and miltefosine resistant L. infantum lines. The overall achievements represent founding concepts to confirm
new targets involved in the parasitic drug resistance and TF mechanisms,
and to consider in perspective the importance of a dual host–guest
pharmacological approach to treat the acute stage of the disease.