STAT3-dependent transactivation of miRNA genes following Toxoplasma gondii infection in macrophage

Abstract

BackgroundThe apicomplexan parasite Toxoplasma gondii can infect and replicate in virtually any nucleated cell in many species of warm-blooded animals; T. gondii has elaborate mechanisms to counteract host-cell apoptosis in order to maintain survival and breed in the host cells.MethodsUsing microarray profiling and a combination of conventional molecular approaches, we investigated the levels of microRNAs (miRNAs ) in human macrophage during T. gondii infection. We used molecular tools to examine Toxoplasma-upregualted miRNAs to revealed potential signal transducers and activators of transcription 3(STAT3) binding sites in the promoter elements of a subset of miRNA genes. We analysed the apoptosis of human macrophage with the functional inhibition of the STAT3-binding miRNAs by flow cytometry.ResultsOur results demonstrated differential alterations in the mature miRNA expression profile in human macrophage following T. gondii infection. Database analysis of Toxoplasma-upregulated miRNAs revealed potential STAT3 binding sites in the promoter elements of a subset of miRNA genes. We demonstrated that miR-30c-1, miR-125b-2, miR-23b-27b-24-1 and miR-17 ~ 92 cluster genes were transactivated through promoter binding of the STAT3 following T. gondii infection. Importantly, functional inhibition of selected STAT3-binding miRNAs in human macropahges increased apoptosis of host cells.ConclusionsA panel of miRNAs is regulated through promoter binding of the STAT3 in human macrophage and these miRNAs are involved in anti-apoptosis in response to T. gondii infection.

Modulation of host immune responses to Toxoplasma gondii by microRNAs

“…Initial global analysis of host miRNA expression following T. gondii infection showed upregulation of 8.3% and downregulation of 4.3% of miRNAs in human macrophages . Also, a subset of miRNAs (miR‐30c‐1, miR‐125b‐2, miR‐23b‐27b‐24‐1 and miR‐17~92 cluster genes) was induced following infection of human macrophages with all three archetypal T oxoplasma strains . Examination of miRNA expression profiles in human neuroepithelioma cells with Toxoplasma infection revealed an upregulation of miR‐132, which is associated with dopamine receptor signalling in the neuropathological processes of infection .…”

“…Many innate immune effectors are controlled by host cell signalling, followed by regulating the overall response to invading protozoa and influencing the consequences of infection. The successful parasite T. gondii may subvert host cell immune pathways as one of its survival strategies …”

Identification of a TNF-α inducer MIC3 originating from the microneme of non-cystogenic, virulent Toxoplasma gondii

“…Acute T. gondii infection initiates M1-dominant polarization of macrophages, which produce high levels of NO and proinflammatory cytokines such as TNF-α and IL-622232829. M1 macrophages destroy intracellular pathogens by releasing NO, which is known to be a major effector molecule in macrophage-mediated cytotoxicity27.…”

STAT3 activation in infection and infection-associated cancer

“…Cai reported that STAT3 mediates a prosurvival pathway by upregulating miRNAs, leading to inhibition of host cells with Toxoplasma infection. Thus, the function of STAT3-binding miRNAs is considered to be an essential apparatus in Toxoplasma biology 49 . Liu et al .…”