OR27

1:Dalhousie University; 2:University of Saskatchewan

A genetic condition affecting humans protects against tuberculosis.  This condition is Gaucher disease.  Zebrafish models of Gaucher disease are resistant to infection with Mycobacterium marinum (M. marinum), while wild-type fish are not.  Also, iPSC-derived macrophages from human Gaucher patients internalize fewer M. tuberculosis than isogenic controls.  Following uptake in Gaucher macrophages, the mycobacteria do not multiply.  

Gaucher disease varies widely in severity and affects tissue macrophages.  It is caused by mutations in the GBA1 gene and subsequent deficiency of its product, the lysosomal enzyme glucocerebrosidase (GCase).  GCase participates in the degradation of complex glycosphingolipids by cleaving glucose off glucosylceramide and glucosylsphingosine.  Mutant GBA1 alleles associated with Gaucher disease code for enzyme forms that are less active than wild-type GCase.  The deficit in GCase activity results in lysosomal accumulation of glucosylceramide and glucosylsphingosine.  In vitro, the latter lipid is toxic to M. marinum and M. tuberculosis. 

The question is now whether chemical models of Gaucher disease also can protect against tuberculosis.  This question has been challenging to address due to the lack of GCase inhibitors that are selective as well as potent.  We have developed irreversible inhibitors of GCase that meet these criteria.  Our inhibitors do not affect the non-lysosomal isoenzyme GBA2 and react with GCase in minutes at nanomolar levels.  These inhibitors can be used to titrate the level of inhibition of GCase and subsequent glucosylsphingosine accumulation, optimizing the toxicity towards mycobacteria.  Altogether, our GCase inhibitors may offer a novel approach for targeting mycobacteria.