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Forward Genetics Screens Using Macrophages to Identify Toxoplasma gondii Genes Important for Resistance to IFN-γ-Dependent Cell Autonomous Immunity
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Forward Genetics Screens Using Macrophages to Identify Toxoplasma gondii Genes Important for Resistance to IFN-γ-Dependent Cell Autonomous Immunity

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p47 GTPases regulate Toxoplasma gondii survival in activated macrophages

Barbara A Butcher1, Robert I Greene, Stanley C Henry

  • 1Dept. of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

Infection and Immunity
|May 24, 2005
PubMed

Insights

Interferon-gamma (IFN-gamma) activates host defenses against Toxoplasma gondii. Specific p47 GTPases, IGTP and LRG-47, are crucial for this parasite resistance by inhibiting intracellular growth within macrophages.

Area of Science:

  • Immunology
  • Cell Biology
  • Parasitology

Background:

  • Interferon-gamma (IFN-gamma) is vital for controlling Toxoplasma gondii infections.
  • The specific host cell factors mediating IFN-gamma's anti-Toxoplasma effects are not fully understood.
  • Previous studies identified IGTP and LRG-47 as essential for in vivo resistance to T. gondii.

Purpose of the Study:

  • To investigate the role of p47 GTPases (IGTP, LRG-47, IRG-47) in IFN-gamma-mediated suppression of T. gondii growth in macrophages.
  • To determine if the in vivo function of these GTPases correlates with their in vitro activity against T. gondii.

Main Methods:

  • Generation of bone marrow-derived macrophages lacking specific GTPases (IGTP, LRG-47, IRG-47).
  • Assessment of IFN-gamma-induced inhibition of T. gondii growth in these knockout macrophages.
  • Confocal microscopy and sucrose density fractionation to determine protein localization.

Main Results:

  • Macrophages deficient in IGTP or LRG-47 showed significantly reduced IFN-gamma-induced inhibition of T. gondii growth.
  • Macrophages lacking IRG-47 exhibited normal inhibition, similar to wild-type cells.
  • IGTP localized to the endoplasmic reticulum and LRG-47 to the Golgi apparatus; neither localized to vacuoles with live T. gondii.

Conclusions:

  • IGTP and LRG-47 are essential for IFN-gamma's ability to inhibit T. gondii growth within macrophages.
  • The in vitro function of IGTP and LRG-47 in suppressing parasite growth correlates with their importance in vivo.
  • These p47 GTPases likely contribute to host resistance against T. gondii by impacting intracellular parasite replication.

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