Destruction of vacuolar pathogens by p47 GTPases

• Applicant: Professor Dr. Jonathan Charles Howard
• Subject Area: Immunology
• Term: from 2002 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5358396

Cell-autonomous resistance to intracellular pathogens is imperfectly understood. The recently-described interferoninducible p47 GTPases are strong candidates for a role in cell-autonomous resistance in the mouse. We have shown that bacterial LPS is also an inducer for p47 GTPases in mouse macrophages. With respect to LPS itself, the planned experiments address the following questions. Firstly, which moiety of LPS is inductive; secondly, through which surface receptor(s) does the inductive signal pass; thirdly, which activation pathway is responsible for the transduction of the signal. We have further shown that the intracellular localisation of g-interferon induced p47 GTPases in macrophages is altered by subsequent LPS stimulation. We will investigate the basis for this behaviour. Post-synthetic modifications of the p47 GTPases and modification of their interacting partners subsequent to LPS stimulation will be sought by biochemical approaches. The relationship between intracellular localisation and bound nucleotide status will be investigated by site-directed mutagenesis of the p47 GTPase, based on the crystal structure. Finally, the significance of the p47 GTPases in interferon- and LPS-induced resistance to Brucella abortus will be investigated.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1110: Innate Immunity