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Toxoplasma gondii inhibits apoptosis via a novel STAT3-miR-17-92-Bim pathway in macrophages

Significance statement

Generally, microbe-infected cells are induced to undergo the intrinsic apoptotic pathway in order to block dissemination of the invaders. However, as a typical intracellular protozoan parasite of warm-blooded vertebrates, Toxoplasma gondii has elaborate mechanisms to counteract host-cell apoptosis in order to multiply and disseminate. We used Toxoplasma gondii TgCtwh3, which has been identified as a strain with the atypical genotype Chinese 1 (ToxoDB#9) and high virulence to mice, to infect human macrophages. Our findings show that TgCtwh3 could inhibit apoptosis in host cells through a novel inhibitory pathway, STAT3- miR-17~92-Bim, which is a precise regulatory mechanism used by Toxoplasma gondii to inhibit apoptosis and to benefit from it for parasite survival. These results further clarify the relationship between Toxoplasma gondii and its host cells and reveal a novel pathway which is an important mechanism in Toxoplasma gondii survival.

 

 

Toxoplasma gondii inhibits apoptosis via a novel STAT3-miR-17-92-Bim pathway in macrophages

Journal Reference

Cai Y1, Chen H2, Mo X3, Tang Y3, Xu X4, Zhang A4, Lun Z5, Lu F5, Wang Y6, Shen J7.

Cell Signal. 2014 Jun;26(6):1204-12.

1Anhui Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University, Hefei, China; Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, China; Department of Immunology, Anhui Medical University, Hefei, China and

2Anhui Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University, Hefei, China; Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China and

3Anhui Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University, Hefei, China and

4Anhui Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University, Hefei, China; The Central Laboratory of Affiliated Provincial Hospital, Anhui Medical University, Hefei, China and

5State Key Laboratory of Biocontrol, School of Life Sciences, and Key Laboratory of Tropical Diseases Control, The Ministry of Education, Zhongshan Medical College, China; Department of Pathogen Biology, Sun Yat-Sen University, Guangzhou, China and

6Department of Pathogen Biology, Nanjing Medical University, Nanjing, China and

7Anhui Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University, Hefei, China. Electronic address: [email protected]

 

Abstract

 In order to accomplish their life cycles, intracellular pathogens, including the apicomplexan Toxoplasma gondii, subvert the innate apoptotic response of infected host cells. However, the precise mechanisms of parasite interference with the apoptotic pathway remain unclear. MicroRNAs (miRNAs) regulate gene expression at the posttranscriptional level. Using Toxoplasma gondii strain TgCtwh3, which was isolated from felids and possesses the predominant genotype China 1 (ToxoDB(#)9) in China, we analyzed the miRNA expression profile of human macrophages challenged with TgCtwh3. The results showed that miR-17-92 miRNA expression was significantly increased and Bim was decreased in TgCtwh3-infected cells. Database analysis of miR-17-92 miRNAs revealed the potential binding sites in the 3’UTR of Bim, one of the crucial effectors of pro-apoptosis. Furthermore, we demonstrated that the promoter of the miR-17-92 gene cluster which encodes miRNAs was transactivated through the promoter binding of the STAT3 following TgCtwh3 infection. Taken together, we describe a novel STAT3-miR-17-92-Bim pathway, thus providing a mechanistic explanation for inhibition of apoptosis of host cells following Toxoplasma gondii infection.

Copyright © 2014 Elsevier Inc. All rights reserved.

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