Role of ASMase in select secretory pathways of macrophages, NK cells, and mast cells

• Antragsteller: Professor Dr. Olaf Utermöhlen
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2002 bis 2008
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5357935

Tumor necrosis factor (TNF) represents an archetype cytokine of the innate immune system that contributes to host resistance to viruses, parasites, fungi, and intracellular bacteria. TNF participates directly in resistance to microbial pathogens by controlling the antimicrobial activity of macrophages. The TNF/TNF receptor system is crucial for the control of L. monocytogenes infections. One of the hallmarks of L. monocytogenes is the early evasion of the phagosome employing a pore forming toxin (Listeriolysin-O, LLO) and C-type phospholipases (PlcA and PlcB). TNF stimulates the activation of a host cell C-type phospholipase, acid sphingomyelinase (ASMase), that is localized in the endolysosomal compartment and likely involved in many kinds of membrane functions including membrane permeability, bending, fusion and fission. By means of this proposal, a possible cooperation of listerial phospholipases and macrophage-derived ASMase with respect to bacterial entry, phagosomal evasion, phagolysosomal fusion and host cell apoptosis will be investigated in vitro and in vivo by using macrophages and mice deficient for ASMase in combination with congenic LLO, PlcA and PlcB deletion mutants of L. monocytogenes. By triggering chemokine production and modulating the expression of vascular cell adhesion molecules TNF orchestrates the recruitment of proinflammatory leukocytes to sites of infection, which provide a link to the adaptive immune response. ASMase through generation of ceramide activates cathepsin D that is involved in antigen processing, cytokine secretion and apoptosis. To unravel a possibly additional role of ASMase for the interplay between innate and adaptive immunity, a mouse Lymphocytic Choriomeningitis Virus (LCMV) infection model will be used. This model promises to be especially revealing because infections with LCMV are controlled by both innate and adaptive immune responses.

• DFG-Verfahren: Schwerpunktprogramme
• Teilprojekt zu: SPP 1110: Angeborene Immunität
• Beteiligte Person: Professor Dr. Martin Krönke