Abstract
BackgroundThe 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.Methodology/Principal FindingsUsing microarray profiling and a combination of conventional molecular approaches we report that Toxoplasma specifically modulates the expression of important host microRNAs during infection. We show that both the primary transcripts for miR-17∼92 and miR-106b∼25 and the pivotal miRNAs that are derived from miR-17∼92 display increased abundance in Toxoplasma-infected primary human cells; a Toxoplasma-dependent up-regulation of the miR-17∼92 promoter is at least partly responsible for this increase. The abundance of mature miR-17 family members, which are derived from these two miRNA clusters, remains unchanged in host cells infected with the closely related apicomplexan Neospora caninum; thus, the Toxoplasma-induced increase in their abundance is a highly directed process rather than a general host response to infection.Conclusions/SignificanceAltered levels of miR-17∼92 and miR-106b∼25 are known to play crucial roles in mammalian cell regulation and have been implicated in numerous hyperproliferative diseases although the mechanisms driving their altered expression are unknown. Hence, in addition to the implications of these findings on the host-pathogen interaction, Toxoplasma may represent a powerful probe for understanding the normal mechanisms that regulate the levels of key host miRNAs.
Highlights
The intracellular protozoan parasite Toxoplasma gondii is a ubiquitous pathogen of warm-blooded animals with approximately one to two billion humans infected [1]
Toxoplasma gondii Alters MiRNA Levels in Host Cells To investigate whether Toxoplasma infection alters the steadystate levels of host miRNAs, we profiled the levels of miRNAs extracted from primary human foreskin fibroblasts (HFFs) during a 24-hour Toxoplasma infection timecourse using miRNA microarrays spotted with duplicate probes that should hybridize to all human, mouse and rat miRNAs included in miRbase v
We focused our attention on 18 microarray spots (9 closely related human and mouse probe sequences that were spotted in duplicate) that displayed comparable increases in hybridization intensities on arrays hybridized with RNA derived from infected HFFs (Figure S1, red boxes); these 18 spots contained probes that hybridized to members of the miR-17 family
Summary
The intracellular protozoan parasite Toxoplasma gondii is a ubiquitous pathogen of warm-blooded animals with approximately one to two billion humans infected [1]. 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 the means by which they do this are not known [3,4,5]. Toxoplasma-infected cell cultures can 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 [8,9,10,11] In addition to these alterations in host cell signaling and cell cycle control, Toxoplasma modulates host cell gene expression. We have investigated whether Toxoplasma modulates the levels of host microRNAs (miRNAs) during infection
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