Dissecting The role of <i>Plasmodium</i> metacaspase-2 in malaria gametogenesis and sporogony

Abstract

The 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. We deleted the MCA-2 gene from <i>Plasmodium berghei</i> genome using a gene knockout strategy to decipher its precise function. This study has identified that MCA-2 plays an important role in parasite transmission since it is critical 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. Furthermore, a study found the two MCA-2 inhibitory molecules known as C-532 and C-533, which remarkably inhibited the MCA-2 activity, abolished the <i>in vitro</i> parasite growth, and also impaired the transmission cycle of <i>P. falciparum</i> and <i>P. berghei</i> in <i>An. stephensi</i>. Our findings indicate that the deletion of MCA-2 hampers the <i>Plasmodium</i> development during erythrocytic and exo-erythrocytic stages, and its inhibition by C-532 and C-533 critically affects the malaria transmission biology.