Deciphering the Role of Copper in Host-Leishmania Relationship

Paul, Rupam (2024) Deciphering the Role of Copper in Host-Leishmania Relationship. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Rupam Paul (18RS102)) 18RS102.pdf - Submitted Version Restricted to Repository staff only Download (11MB)

Abstract

Copper is an essential micronutrient for all life forms. However, in excess, it becomes toxic. Such toxic properties of copper are known to be utilized by host species against various pathogenic invasions. The study explores the role of copper in host-pathogen interaction using Leishmania-macrophage model. The work has led to the identification of a novel copper transporter, LmATP7 in Leishmania major that is crucial for its infectivity. It further reveals an interplay between the macrophage copper transporter, ATP7A (channelising copper to pathogen compartments) and the pathogenic counterpart, LmATP7, neutralising the toxic effect by exporting the metal out. Additionally, Leishmania utilizes a variety of manipulative measures to lower the host-induced copper-stress. Leishmania infection induces deglycosylation and degradation of macrophage ATP7A. The pathogenic infection results in downregulation of the macrophage copper importer, CTR1 and alters its cysteine redox status that destabilizes its dimeric conformation. In the mouse model of infection, an increase in systemic bioavailable copper is observed in infected animals. Heart and liver act as the major organs of diverting their copper reserves to systemic circulation to fight-off infection. Remarkably, Leishmania infected animals fed with high copper diet exhibited significant delay in lesion development as compared to controls or animals fed on copper-limiting diet. The study explores and establishes the reciprocal mechanism of manipulation of copper homeostasis pathway by host and Leishmania to gain respective advantages in host-pathogen interaction.

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