ROLE OF METACASPASE IN MALARIA TRANSMISSION BIOLOGY

Abstract

Intro: A family of apicomplexan-specific proteins contains caspases–like proteins called “metacaspases”. These enzymes are present in the malaria parasite but absent in human, therefore, these can be explored as potential drug targets to combat malaria. Methods: In our study, we deleted metacaspase-2 (MCA-2) gene from Plasmodium berghei (mouse model) genome using a gene knockout strategy to decipher its precise function. Further did inhibition study to find out ki/ Ic50 of this enzyme. Findings: This study has identified that MCA-2 plays an important role in parasite transmission since it is important for the formation of gametocytes and for maintaining an appropriate number of infectious sporozoites required for sporogony. It is noticeable that a significant reduction in gametocyte, oocysts, ookinete and sporozoites load along with a delay in hepatocytes invasion were observed in the MCA-2 knockout parasite. Our study also found the two MCA-2 inhibitory molecules known as C-532 and C-533, which remarkably inhibited the MCA-2 activity, abolished the in vitro parasite growth. Conclusion: The specific inhibitors impaired the transmission cycle of P. falciparum and P. berghei in An. stephensi. Our findings indicate that the deletion of MCA-2 hampers the Plasmodium development during erythrocytic and exo-erythrocytic stages, and its inhibition by C-532 and C-533 critically affects malaria transmission biology.