Research Article: Toxoplasma gondii Infection Specifically Increases the Levels of Key Host MicroRNAs

Date Published: January 15, 2010

Publisher: Public Library of Science

Author(s): Gusti M. Zeiner, Kara L. Norman, J. Michael Thomson, Scott M. Hammond, John C. Boothroyd, Mauricio Martins Rodrigues. http://doi.org/10.1371/journal.pone.0008742

Abstract: The apicomplexan parasite Toxoplasma gondii can infect and replicate in virtually any nucleated cell in many species of warm-blooded animals; thus, it has evolved the ability to exploit well-conserved biological processes common to its diverse hosts. Here we have investigated whether Toxoplasma modulates the levels of host microRNAs (miRNAs) during infection.

Partial Text: The intracellular protozoan parasite Toxoplasma gondii is a ubiquitous pathogen of warm-blooded animals with approximately one to two billion humans infected [1]. While infections in immunocompetent adults are typically subclinical, infection persists for the life of the host, and serious disease can occur in fetal infections and in primary or recrudescent infection of immunocompromised persons. During host cell invasion, Toxoplasma uses a specialized set of secretory organelles to inject parasite-derived effector molecules into its host cell [2]. Some of these effectors are known to interfere with host cell signaling pathways and alter host defenses although the means by which they do this are not known [3]–[5]. Toxoplasma appears to block apoptotic responsiveness in its host cells at myriad points [6] and to co-opt host apoptotic signaling pathways as an environment-sensing mechanism [7]. Toxoplasma-infected cell cultures can also cede control of their cell cycle, progressing through G1/S and halting at G2/M and Toxoplasma attaches to, and invades host cells in S phase up to 4 times more efficiently than host cells in G1 [8]–[11]. In addition to these alterations in host cell signaling and cell cycle control, Toxoplasma specifically modulates host cell gene expression. Changes to the Toxoplasma-infected host transcriptome have been interrogated by expression-profiling and the data demonstrate that 24 hours post-infection, upwards of 15% of host mRNAs display altered abundance relative to uninfected cells [12]; similarly, quantitative analysis of the host proteome during Toxoplasma infection showed that the abundance of many host proteins is modulated in expression by Toxoplasma[13].

The results presented here demonstrate that Toxoplasma infection specifically drives an increase of 2–3 fold in the levels of mature miR-17∼92-derived miRNAs in primary human foreskin fibroblasts. The mature miRNAs encoded by miR-17∼92 and its paralog miR-106b∼25 play important roles in mammalian biology. MiR-17∼92 is crucial in development, as mice harboring a homozygous deletion of miR-17∼92 die shortly after birth due to pulmonary and cardiac defects and develop abnormal B-cell lymphocytes [32]. In adult animals, miR-17∼92 and miR-106b∼25 have been shown to influence the functionally intertwined pathways of apoptosis and G1/S cell cycle progression by targeting multiple components of each pathway [20]. The importance of these functions have been demonstrated by showing that retroviral overexpression of a cassette containing miR-17, miR-18 and miR-19 in mice results in c-Myc-induced lymphoma [29]. More subtly, transgenic mice that have been engineered to overexpress miR-17∼92 by 2-fold in lymphocytes develop lymphoproliferative disease and autoimmunity and die prematurely, phenotypes that were shown to be partially a consequence of the translational repression of PTEN and Bim [30]. Hence, even relatively modest increases in the levels of miR-17∼92, of a magnitude less even than seen here with Toxoplasma infection, have profound biological consequences in vivo.

Source:

http://doi.org/10.1371/journal.pone.0008742

 

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