Ben Rosenfeld
“Characterizing the role of lysosomal trafficking in Drosophila innate immune activation”
Benjamin H. Rosenfeld, Steven J. Del Signore and Avital A. Rodal
Brandeis / Biology, Chemistry
Hosted by Rodal's Lab
Abstract
Lowe Syndrome is an X-linked recessive disorder characterized by congenital cataracts, intellectual disability, seizures and kidney defects, and is caused by mutation in the gene OCRL. How loss of OCRL causes such a diverse range of symptoms is poorly understood.
To address this question using an in vivo model, we generated Drosophila lacking the OCRL homolog, docrl. Surprisingly, we found that docrl mutants exhibited strong activation of the innate immune system, likely due to excess production and secretion of the immune signal Spaetzle (Spz). In hemocytes, which are macrophage-like innate immune cells, we found multiple membrane trafficking phenotypes, including endocytic defects, altered early, late and recycling compartments, and defective lysosomal trafficking.
Here, we tested the hypothesis that lysosomal fusion specifically plays a role in the immune phenotype observed in docrl mutants. Using the Drosophila model, we have increased immune activation, inhibited lysosomal fusion and inactivated lysosome function in hemocytes expressing GFP-tagged Spz. In preliminary results, we found that inhibition of lysosomal fusion increases intracellular Spz, but neither inhibition of lysosomal fusion nor inactivation of the lysosome cause excessive immune activation typical of docrl mutants. Research has shown there is strong evidence for a link between inflammation, innate immunity and epilepsy. Therefore, determining the underlying mechanism for the immune phenotype observed in docrl mutants could lead to a better understanding of the causes of seizure symptoms in Lowe Syndrome patients. In the immediate future, we will manipulate S2 cells to investigate the secretion levels of Spz to further understand the role of lysosomal trafficking on the immune phenotype observed in docrl mutants.
Support
SMURF (Summer MRSEC Undergrad Research Fellowship)