Guanylate-binding Protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against toxoplasma gondii

Qin, A; Lai, D; Liu, Q; Huang, W; Wu, Y; Chen, X; Yan, S; Xia, H; Hide, G; Lun, Z; Ayala, F; Xiang, A

Abstract

Mesenchymal stromal cells (MSCs) have recently been shown to play important roles in mammalian host defenses against intracellular pathogens, but the molecular mechanism still needs to be clarified. We confirmed that human MSCs (hMSCs) pre-stimulated with IFN-γ showed a significant and dose-dependent ability to inhibit the growth of two types of Toxoplasma gondii (type I strain RH/GFP or type II strain PLK/RED). However, in contrast to previous reports, the anti-T. gondii activity of hMSCs was not mediated by indoleamine 2,3-dioxygenase (IDO). Genome-wide RNA-seq analysis revealed that IFN-γ increased the expression of the p65 family of guanylate-binding proteins (hGBPs) in hMSCs, especially hGBP1. To analyze the functional role of hGBPs, stable knockdowns of hGBP1, -2, -5 in hMSCs were established using a lentiviral transfection system. hGBP1 knockdown in hMSCs resulted in a significant loss of the anti-T. gondii host defense property, compared with hMSCs infected with non-targetted control sequences. hGBP2 and -5 knockdowns had no effect. Moreover, the hGBP1 accumulation on the parasitophorous vacuole (PV) membranes of IFN-γ-stimulated hMSCs might protect against T. gondii infection. Taken together, our results suggest that hGBP1 plays a pivotal role in anti-T. gondii protection of hMSCs and may shed new light on clarifying the mechanism of host defense properties of hMSCs.

• Journal Article Type: Article
• Acceptance Date: Dec 9, 2016
• Online Publication Date: Jan 25, 2017
• Publication Date: Feb 7, 2017
• Deposit Date: Dec 21, 2016
• Publicly Available Date: Dec 21, 2016
• Journal: Proceedings of the National Academy of Sciences of the United States of America (PNAS)
• Electronic ISSN: 1091-6490
• Publisher: National Academy of Sciences
• Volume: 114
• Issue: 6
• Pages: 1365-1370
• DOI: https://doi.org/10.1073/pnas.1619665114
• Publisher URL: http://dx.doi.org/10.1073/pnas.1619665114
• Related Public URLs: https://www.ncbi.nlm.nih.gov/pubmed/28123064; http://www.salford.ac.uk/environment-life-sciences/els-academics/geoff-hide; http://www.pnas.org/
• Additional Information: Funders : China Postdoctoral Science Foundation;National Basic Research Program of China;National Natural Science Foundation of China;Key Scientific and Technological Projects of Guangdong Province; Projects : Guanylate-binding Protein 1 (GBP1) Contributes to the Immunity of Human Mesenchymal Stromal Cells against Toxoplasma gondii; Grant Number: 2015A030310428; Grant Number: 973 Program, No.:2010CB350000; Grant Number: 81425016, 31472058; Grant Number: 2014B020226002