Released Parasite-Derived Kinases as Novel Targets for Antiparasitic Therapies.

Anne Silvestre,Najma Rachidi,Sharvani Shrinivas Shintre

doi:10.3389/fcimb.2022.825458

Abstract

The efficient manipulation of their host cell is an essential feature of intracellular parasites. Most molecular mechanisms governing the subversion of host cell by protozoan parasites involve the release of parasite-derived molecules into the host cell cytoplasm and direct interaction with host proteins. Among these released proteins, kinases are particularly important as they govern the subversion of important host pathways, such as signalling or metabolic pathways. These enzymes, which catalyse the transfer of a phosphate group from ATP onto serine, threonine, tyrosine or histidine residues to covalently modify proteins, are involved in numerous essential biological processes such as cell cycle or transport. Although little is known about the role of most of the released parasite-derived kinases in the host cell, they are examples of kinases hijacking host cellular pathways such as signal transduction or apoptosis, which are essential for immune response evasion as well as parasite survival and development. Here we present the current knowledge on released protozoan kinases and their involvement in host-pathogen interactions. We also highlight the knowledge gaps remaining before considering those kinases - involved in host signalling subversion - as antiparasitic drug targets.

Highlights

The efficient manipulation of their host cell is an essential feature of intracellular parasites, which they achieve by secreting effectors to maintain their replicative niche within the host cell and to hijack important host pathways
Nucleoside Diphosphate Kinase (Ndk) participates in the host purine salvage by protozoan parasites by utilizing extracellular ATP (eATP) to produce other nucleoside triphosphate (NTP) such as GTP (Kolli et al, 2008) These functions might be conserved in T. cruzi and T. gondii, which release Ndk
Additional host proteins phosphorylated by L-Casein kinase 1 (CK1).2 were identified (Smirlis et al, 2022). Several pathways, such as apoptosis, actin skeleton organisation or RNA processing were shown to be potentially regulated by L-CK1.2, which corresponds to pathways altered during Leishmania infection (Smirlis et al, 2020). These findings suggest that L-CK1.2 might replace human CK1 and phosphorylate host proteins to modify the immune status of the host cell

Summary

Introduction

The efficient manipulation of their host cell is an essential feature of intracellular parasites, which they achieve by secreting effectors to maintain their replicative niche within the host cell and to hijack important host pathways. Parasites release virulence factors either as soluble molecules or inside extracellular vesicles (EVs), leading to the modification of the biological and immune functions of their host cell to ensure their survival (Silverman et al, 2010b; Regev-Rudzki et al, 2013). Little is known about the mechanisms involved in cargo selection of these EVs. Leishmania HSP100 has a strong impact on protein cargo composition: its deletion affects the immune status of the host cell and parasite survival (Silverman et al, 2011).

Results

Conclusion