Role of sphingolipids in host-pathogen interactions during Salmonella infection

Encounters between immune cells and invading bacteria involve multiple host-pathogen interactions with different attack strategies and counter-defenses by both sides. Salmonella, a gram-negative intracellular pathogen, targets mostly macrophages as its hosts, in which it sustains a habitable environment in a salmonella containing vacuole (SCV).

Salmonella expresses SrfJ, a suggested T3SS effector with extremely high peptide homology to the human lysosomal glucosylceramidase (GCase) GBA.

Using fluorescent microscopy and immuno-TEM we observed natural secretion of SrfJ from the SCV into the macrophage. We demonstrated that SrfJ is active as a GCase to a much less extent, and in a completely different pH than GBA, more adequate to the cytoplasm environment. Despite a very low autonomous activity, SrfJ had a remarkable additive effect to GBA`s activity in vitro.

Glycosphingolipids serve as self-antigens required for iNKT cell maturation, survival and maintenance. iNKT cells play a role in host defense against bacterial infection.

Our recent work demonstrates changes in the sphingolipid’s metabolism of the host, following Salmonella infection. Infection of human PBMCs by wild type salmonella resulted in higher CFU than ΔSrfJ salmonella. Moreover, cells that were infected by ΔSrfJ salmonella expressed and secreted more IFN-γ than cells that were infected by WT salmonella, suggesting that SrfJ is crucial for interfering with the immune response.

We suggest that SrfJ disrupts macrophage-iNKT early cross-talk by manipulating the sphingolipids pool of the macrophage through interaction with its human homolog GBA, thus increasing Salmonella survival rate. This may be done by.