title: Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses.
abstract: Malaria infection triggers pro-inflammatory responses in humans that are detrimental to host health. Parasite-induced enhancement in cytokine levels correlate with malaria-associated pathologies. Here we show that parasite tyrosyl-tRNA synthetase (PfTyrRS), a housekeeping protein translation enzyme, induces pro-inflammatory responses from host immune cells. PfTyrRS exits from the parasite cytoplasm into the infected red blood cell (iRBC) cytoplasm, from where it is released into the extracellular medium on iRBC lysis. Using its ELR peptide motif, PfTyrRS specifically binds to and internalizes into host macrophages, leading to enhanced secretion of the pro-inflammatory cytokines TNF-α and IL-6. PfTyrRS-macrophage interaction also augments expression of adherence-linked host endothelial receptors ICAM-1 and VCAM-1. Our description of PfTyrRS as a parasite-secreted protein that triggers pro-inflammatory host responses, along with its atomic resolution crystal structure in complex with tyrosyl-adenylate, provides a novel platform for targeting PfTyrRS in anti-parasitic strategies.
authors: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110 067, India.
authors: Tarun Kumar
authors: TK
authors: Bhatt
authors: Sameena
authors: S
authors: Khan
authors: Ved Prakash
authors: VP
authors: Dwivedi
authors: Mudassir Meraj
authors: MM
authors: Banday
authors: Arvind
authors: A
authors: Sharma
authors: Anmol
authors: A
authors: Chandele
authors: Noelia
authors: N
authors: Camacho
authors: Lluís
authors: L
authors: Ribas de Pouplana
authors: Yang
authors: Y
authors: Wu
authors: Alister G
authors: AG
authors: Craig
authors: Antti Tapani
authors: AT
authors: Mikkonen
authors: Alexander Gerd
authors: AG
authors: Maier
authors: Manickam
authors: M
authors: Yogavel
authors: Amit
authors: A
authors: Sharma
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008288:Malaria / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014448:Tyrosine-tRNA Ligase / Q000276:immunology* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D014448:Tyrosine-tRNA Ligase