IGTP is necessary for Toxoplasma Vacuolar Disruption and Induces Parasite Egression in IFN{gamma} Stimulated Astrocytes

Infect Immun. 2008 Sep 2. [Epub ahead of print]

IGTP is necessary for Toxoplasma Vacuolar Disruption and Induces Parasite Egression in IFN{gamma} Stimulated Astrocytes

Melzer T, Duffy A, Weiss LM, Halonen SK.

Dept. of Microbiology, Montana State University, Bozeman, MT. 59717 U.S.A.; Dept. of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO. 80523; Dept. of Pathology, Albert Einstein College of Medicine, Bronx, NY. 10460.

Toxoplasma gondii is a common central nervous system infection in individuals with immunocompromised immune systems, such as AIDS patients. Interferon-gamma (IFNgamma) is the main cytokine mediating protection against T. gondii. Our previous studies found IFNgamma significantly inhibits T. gondii in astrocytes via an IGTP dependent mechanism. The IGTP-dependent- IFNgamma stimulated inhibition is not understood but recent studies found IGTP induces disruption of the parasitophorous vacuole (PV) in macrophages. In the current study, we have further investigated the mechanism of IFNgamma inhibition and the role of IGTP in the vacuolar disruption in murine astrocytes. Vacuolar disruption was found to be dependent upon IGTP as PV disruption was not observed in IGTP deficient astrocytes (IGTP(-/-)) and PV disruption could be induced in IGTP(-/-) astrocytes transfected with IGTP. Live cell-imaging studies using GFP-IGTP found IGTP is delivered to the PV via host cell ER early after invasion and that IGTP condenses into vesicular-like structures on the vacuole, just prior to PV disruption, suggesting IGTP is involved in PV disruption. Intravacuolar movement of the parasite occurred just prior to PV disruption. In some instances IFNgamma induced parasite egression. Electron microscopy and immunofluorescence studies indicate host cell ER fuses with the PV prior to vacuolar disruption. Based upon these results, we postulate a mechanism by which ER/PV fusion is a crucial event in PV disruption. Fusion of the ER with the PV, releasing calcium into the vacuole may also be the mechanism by which intravacuolar parasite movement and IFNgamma induced parasite egression occurs.

PMID: 18765738 [PubMed - as supplied by publisher]