title: Phosphorylation of Translation Initiation Factor 2-Alpha in Leishmania donovani under Stress Is Necessary for Parasite Survival.
abstract: The transformation of Leishmania donovani from a promastigote to an amastigote during mammalian host infection displays the immense adaptability of the parasite to survival under stress. Induction of translation initiation factor 2-alpha (eIF2α) phosphorylation by stress-specific eIF2α kinases is the basic stress-perceiving signal in eukaryotes to counter stress. Here, we demonstrate that elevated temperature and acidic pH induce the phosphorylation of Leishmania donovani eIF2α (LdeIF2α). In vitro inhibition experiments suggest that interference of LdeIF2α phosphorylation under conditions of elevated temperature and acidic pH debilitates parasite differentiation and reduces parasite viability (P < 0.05). Furthermore, inhibition of LdeIF2α phosphorylation significantly reduced the infection rate (P < 0.05), emphasizing its deciding role in successful invasion and infection establishment. Notably, our findings suggested the phosphorylation of LdeIF2α under H2O2-induced oxidative stress. Inhibition of H2O2-induced LdeIF2α phosphorylation hampered antioxidant balance by impaired redox homeostasis gene expression, resulting in increased reactive oxygen species accumulation (P < 0.05) and finally leading to decreased parasite viability (P < 0.05). Interestingly, exposure to sodium antimony glucamate and amphotericin B induces LdeIF2α phosphorylation, indicating its possible contribution to protection against antileishmanial drugs in common use. Overall, the results strongly suggest that stress-induced LdeIF2α phosphorylation is a necessary event for the parasite life cycle under stressed conditions for survival.
authors.affiliation: Division of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
authors.forename: Kumar
authors.initials: K
authors.lastname: Abhishek
authors.affiliation: Division of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
authors.forename: Abul Hasan
authors.initials: AH
authors.lastname: Sardar
authors.affiliation: Department of Microbiology, All India Institute of Medical Sciences, Phulwarisharif, Patna, Bihar, India.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Das
authors.affiliation: Division of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
authors.forename: Ayan Kumar
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Division of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
authors.forename: Ruby
authors.initials: R
authors.lastname: Singh
authors.affiliation: National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park, Hajipur, Vaishali, Bihar, India.
authors.forename: Savita
authors.initials: S
authors.lastname: Saini
authors.affiliation: Division of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Mandal
authors.affiliation: Division of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
authors.forename: Sudha
authors.initials: S
authors.lastname: Verma
authors.affiliation: Division of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
authors.forename: Bidyut
authors.initials: B
authors.lastname: Purkait
authors.affiliation: Department of Bioinformatics, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
authors.forename: Manas Ranjan
authors.initials: MR
authors.lastname: Dikhit
authors.affiliation: Division of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India drpradeep.das@gmail.com.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Das
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006358:Hot Temperature; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000494:pharmacology; D007893:Leishmania donovani / Q000472:pathogenicity / Q000502:physiology*; D007896:Leishmaniasis / Q000378:metabolism / Q000469:parasitology*; D008018:Life Cycle Stages; D051379:Mice; D018384:Oxidative Stress; D010766:Phosphorylation; D015800:Protozoan Proteins / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: C576403:7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine; D015852:Eukaryotic Initiation Factor-2; D007211:Indoles; D015800:Protozoan Proteins; D006861:Hydrogen Peroxide; D000225:Adenine
keywords: GSK2606414; LdeIF2α phosphorylation; Leishmania survival; oxidative stress; pH stress; temperature stress