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: Tarun Kumar Bhatt, Sameena Khan, Ved Prakash Dwivedi, Mudassir Meraj Banday, Arvind Sharma, Anmol Chandele, Noelia Camacho, Lluís Ribas de Pouplana, Yang Wu, Alister G Craig, Antti Tapani Mikkonen, Alexander Gerd Maier, Manickam Yogavel, Amit Sharma
• Journal: Nature communications (Nat Commun) Vol. 2 Pg. 530 (Nov 08 2011) ISSN: 2041-1723 [Electronic] England
• PMID: 22068597 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Interleukin-6
• Tumor Necrosis Factor-alpha
• Tyrosine-tRNA Ligase

Topics

• Animals
• Blotting, Western
• Cell Line
• Cells, Cultured
• Cytokines (metabolism)
• Erythrocytes (immunology, parasitology)
• Humans
• Interleukin-6 (metabolism)
• Macrophages (metabolism)
• Malaria (immunology, metabolism, parasitology)
• Mice
• Tumor Necrosis Factor-alpha (metabolism)
• Tyrosine-tRNA Ligase (immunology, metabolism)