Role of neutral sphingomyelinase in mycobacterial infections

• Applicants: Dr. Heike Grassmé; Professor Dr. Erich Gulbins
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 242127429

Tuberculosis is one of the most common and important infections woldwide. In the first funding period we demonstrated that neutral sphingomyelinase 2 (Nsm, Smpd3) regulates the release of reactive oxyen species (ROS) in macrophages upon infection with Bacillus Calmette-Guérin (BCG). ROS in turn suppress autophagy in BCG-infected macrophages in vitro and in vivo; this suppression allows the pathogen to survive within macrophages. These findings indicate that the Nsm/ceramide system plays an important role in the pathogen attack on the host. Additional preliminary findings show that BCG co-localizes with and regulates Rac-1 via Nsm, and this pathway may finally result in the BCG-induced release of ROS. In addition, we identified several other pathways that are triggered by BCG via the activation of Nsm. These pathways include the upregulation and translocation of caveolin-1 to mitochondria, the formation of sphingosine in lysosomes, and the activation of beta-1-integrins that mediate the formation of granuloma and the regulation of several novel proteins that bind to ceramide and sphingosine when macrophages are infected with BCG. We will now (i) define the mechanisms that mediate the regulation of autophagy by Nsm after BCG infections, (ii) characterize proteins that bind to ceramide in BCG-infected cells, (iii) define the function of Nsm-regulated mitochondrial caveolin-1 in the infection process, (iv) characterize the role of Nsm in the formation of granulomas and the regulation of integrin functions, and, finally, (v) study the role of lysosomal sphingosine in BCG infections in vitro and in vivo.

• DFG Programme: Research Units
• Subproject of: FOR 2123: Sphingolipid Dynamics in Infection Control