Targeting calcium signaling in parasitic worms

The parasitic flatworm Schistosoma mansoni and its relatives S. haematobium and S. japonicum infect tens of millions of people in Africa, Asia, and South America. Although treatment with praziquantel is currently effective, additional treatment options would be desirable. Dr. Ana Eliza Zeraik’s preliminary experiments revealed detectable differences in cellular calcium signaling between S. mansoni and in humans, which she hopes to exploit to find new drug targets for the treatment of schistosomiasis.

In both, humans and flatworms, calcium flows when the regulatory molecule STIM activates the calcium channel ORAI. Yet, there are important differences. For example, human STIM can activate the schistosome ORAI channel, but not vice versa. Correspondingly, regions of the protein sequences that are functionally important in human STIM and ORAI are not conserved in schistosome STIM and ORAI. Dr. Zeraik cloned the genes encoding S. mansoni STIM and ORAI at her home institution in Brazil. She came to LJI specifically to carry out cellular studies on the schistosome STIM-ORAI pathway, and to evaluate the possibility of targeting the pathway to treat schistosomiasis.

Dr. Zeraik’s immediate goal is to develop a sensitive, high-troughput assay to screen chemical libraries for compounds that either specifically block the normal function of schistosome ORAI channels, or compounds that activate excessive calcium influx through schistosome ORAI channels. In whole worms, compounds in the former class would be expected to impair normal physiological processes, whereas compounds in the latter group would lead to massive cell death.

In the long term, the assay(s) developed in this SPARK Grant project, together with Dr. Zeraik’s biochemical and cell-biological characterization of S. mansoni STIM and ORAI, would form a strong foundation for a joint grant application by LJI and the Universidade de Sao Paulo to continue the work. If Dr. Zeraik’s experiments are successful, the same approach might be applicable to parasitic diseases caused by other flatworm, e.g. tapeworms, or roundworms, which cause river blindness or filariasis.