Dynamicity in Host Metabolic Adaptation Is Influenced by the Synergistic Effect of Eugenol Oleate and Amphotericin B During Leishmania donovani Infection In Vitro.

Amrita Kar,Avanthika Kumar,Adithyan Jayaraman,Santanu Kar Mahapatra

doi:10.3389/fcimb.2021.709316

Amrita Kar, Avanthika Kumar + Show 2 more

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https://doi.org/10.3389/fcimb.2021.709316

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Abstract

Immune metabolic adaptation in macrophages by intracellular parasites is recognized to play a crucial role during Leishmania infection. However, there is little accessible information about changes in a metabolic switch in L. donovani infected macrophages. In previous studies, we have reported on the anti-leishmanial synergic effect of eugenol oleate with amphotericin B. In the present study, we demonstrated that glycolytic enzymes were highly expressed in infected macrophages during combinatorial treatment of eugenol oleate (2.5 µM) and amphotericin B (0.3125 µM). Additionally, we found that the biphasic role in arachidonic acid metabolite, PGE2, and LTB4, is released during this treatment. In vitro data showed that COX-2 mediated PGE2 synthesis increased significantly (p<0.01) in infected macrophages. Not only was the level of prostaglandin synthesis decreased 4.38 fold in infected macrophages after treatment with eugenol oleate with amphotericin B. The mRNA expression of PTGES, MPGES, and PTGER4 were also moderately expressed in infected macrophages, and found to be decreased in combinatorial treatment. In addition, NOS2 expression was activated by the phosphorylation of p38MAPK when combination-treated macrophages were promoted to kill intracellular parasites. The findings of the present study indicate that the synergism between eugenol oleate and amphotericin B could play an important role in immune metabolism adaptation with a concomitant increase in host immune response against the intracellular pathogen, L. donovani.

Highlights

Visceral leishmaniasis (VL) is caused by the intramacrophagic protozoan parasite of Leishmania donovani and L. infantum
We evaluated the expression of glucose transporter 1 (GLUT-1), isoforms of hexokinase (HK1, HK2, and HK3), phosphofructokinase 2 (PFKM), 6-phosphofructo-2-kinase/ fructose- 2,6-biphosphatase 3 (PFKB3), and lactate dehydrogenase A (LDHA) transcripts
The expression was analyzed in BALB/c derived peritoneal macrophages challenged with stationary phase L. donovani parasites to establish the mechanisms accountable for energy metabolic profile recognition

Summary

Introduction

Visceral leishmaniasis (VL) is caused by the intramacrophagic protozoan parasite of Leishmania donovani and L. infantum. Promastigotes are phagocytosed by macrophages and differentiated into intracellular amastigotes This reciprocity between parasite proliferation and host immunological responses is pivotal for infection establishment and disease amelioration (Gupta et al, 2021). Macrophage polarization can switch in response to the endogenous stimuli during infection and signals both pathogenic and protective functions (Mills, 2012; Boche et al, 2013). The procedure of macrophage polarization is regulated by metabolic reprogramming with bioenergetics demands to keep obligatory immunological functions. This cellular metabolic signaling relies on the consumption of carbohydrates, fatty acids, proteins, or amino acids (O’Neill and Pearce, 2016). The adaptation in metabolic shifting during leishmaniasis could implicate an important target to elicit host immune responses

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