Image from Eva Frickel's lab

Eva Frickel : Ubiquitin-mediated control of Toxoplasma gondii

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During bacterial clearance an initial cellular recognition event marks bacteria or the bacterial inclusion with ubiquitin. This ubiquitination event can either lead to the degradation of the cargo or to signaling events inside the host cell. Whether ubiquitin-driven host defence played a role in Toxoplasma control had been unclear.

Toxoplasma gondii, the causative agent of toxoplasmosis, is the most prevalent persistent human parasitic infection. The obligate intracellular parasite can invade any nucleated cell residing as a tachyzoite in a parasitophorous vacuole (PV). Gamma interferon (IFNγ) produced mainly by CD8 T cells is the major cytokine controlling Toxoplasma by upregulating host effector defences. We currently study the IFNγ-dependent effector responses against Toxoplasma driven by ubiquitin and guanylate binding proteins (GBPs) and characterise CD8 T cell responses during chronic Toxoplasma gondii infection.

During bacterial clearance an initial cellular recognition event marks bacteria or the bacterial inclusion with ubiquitin. This ubiquitination event can either lead to the degradation of the cargo or to signaling events inside the host cell. Whether ubiquitin-driven host defence played a role in Toxoplasma control had been unclear.

Murine cells

We find that in mouse embyonic fibroblasts the PV of type II and not type I Toxoplasma is ubiquitinated in an IFNγ-dependent fashion. Most of the ubiquitin is of the K63 and K48 linkage.

Ubiquitin

Human cells

IFNγ stimulation of Human umbilical vain endothelial cells (HUVEC) leads to ubiquitin dependent acidification of Toxoplasma type II parasitophorous vacuoles.

Ubiquitin

The ubiquitin linkage found around the PV is predominantely of the K63 type and the recruited ubiquitin-binding protein p62 is able to contribute to the restriction of the parasite.

Ubiquitin

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Future questions for the ubiquitin-mediated control ofToxoplasma in human cells:

How is the acidic PV (APV) generated? What Toxoplasma factors mediate the evasion of type I parasites from this pathway? What E3 ligases deposit the ubiquitin? What are the roles of p62 and NDP52 in Toxoplasma restriction?