Toxoplasma gondii remodels the cis -regulatory landscape of infected human host cells

Abstract

Toxoplasma gondii (T. gondii) is an obligate intracellular parasite with a unique ability to infect any nucleated cell of any warm-blooded animal. It is one of the world's most successful parasites as a result of its broad host range, high infection rates and abilities to co-exist with its host. T. gondii is the causative agent of the disease Toxoplasmosis which is generally asymptomatic in most individuals, but can be life threatening in immunocompromised and fetal hosts. As a consequence of the ubiquitous nature of this pathogen, developing a single therapeutic agent against T. gondii has been difficult, and the currently available drugs against T. gondii have severe side effects and are poorly tolerated. The life-threatening nature of this pathogen, and the lack adequate treatment options makes studies of both T. gondii and its interactions with its host essential to maintain control over this deadly pathogen.;It has previously been shown that a T. gondii infection causes the dysregulation of host genes involved in inflammation, apoptosis, metabolism, cell growth and differentiation. We hypothesized that T. gondii modifies transcriptional regulation of the host in order to co-opt host processes during the infection. The mechanisms by which Toxoplasma gondii alters the expression of genes in infected host cells are not understood. We focused on studying how host transcriptional regulatory processes respond to T. gondii infection. Genome-wide studies of cytosine modifications in the host genome revealed a global loss in 5-hydroxymethylation, which could be attributable to the host cell switching to aerobic glycolysis.;The landscape of transposase-accessible chromatin is also altered by infection, with both gains and losses of loci of open chromatin enriched in proximity to transcriptionally altered genes. We demonstrate that these host chromatin changes occur at loci with redistribution of c-Fos transcription factor binding. We conclude that a T. gondii infection influences both host cell metabolism and transcriptional regulation, the latter mediated through transcription factor retargeting to modify the cis-regulatory landscape of the host cell.