Research Area B: Senescence of Membranes and Age-related Impairment of Pathogen Defense

The immune system deteriorates with age, thereby rendering the aged less able to mount an immune response following infectious challenge. Immunosenescence is not only mediated by impaired adaptive immunity but also brought about by dysfunction of the innate immune system. Many innate defense mechanisms such as cell-surface receptor signaling, phagocytosis, phagosomal maturation and fusion with lysosomes, and finally autophagy are membranebound events. Within membranes, ceramide serves as the basic molecule for the synthesis of complex sphingolipids, which segregate in membranes to large sphingolipid-cholesterolenriched membrane platforms. These rafts not only cluster receptor molecules, but also critically regulate uptake of bacterial and viral pathogens. Strikingly, all isoforms of ceramide synthase have been identified as mammalian homologs of yeast longevity assurance genes (Lass), proteins that regulate lifespan provoking the hypothesis that age-related changes of sphingolipid composition of membranes cause functional deficits of innate immunity.
Research area B will further the understanding of the impact of aging membranes on key processes of host defense mechanisms against microbial pathogens including cytokine receptor signaling, pathogen uptake, and autophagy. As an integrated experimental approach, transgenic mice with inducible, tissue-specific deficiencies in ceramide synthase isoforms will be generated and challenged with specific pathogens. Based on the expected insights into the functional impact of altered sphingolipid composition of membranes, therapeutic strategies will be designed to correct age-related membrane dysfunctions

Coordinator:

Prof. Dr. Martin Krönke,
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene
 
email: m.kroenke(at)uni-koeln(dot)de