Dissecting The role of Plasmodium metacaspase-2 in malaria gametogenesis and sporogony

Emerg Microbes Infect. 2022 Dec;11(1):938-955. doi: 10.1080/22221751.2022.2052357.


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 Plasmodium berghei 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 in vitro parasite growth, and also 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 the malaria transmission biology.

Keywords: An. stephensi; Malaria; Plasmodium transmission; gametogenesis; metacaspase; ookinete; specific inhibitor; sporogony.

MeSH terms

  • Animals
  • Gametogenesis
  • Humans
  • Malaria* / parasitology
  • Plasmodium berghei / genetics
  • Protozoan Proteins* / genetics
  • Protozoan Proteins* / metabolism
  • Sporozoites / metabolism


  • Protozoan Proteins

Grant support

This work has been supported by DST (TNT/SWISS/SNSF/P-01/2016) and ICMR-NIMR Intramural grant (PHB/NIMR/EC/2020/148) sanctioned to KCP and ICMR-SRF and PDF (80/950/2015-ECD-I)/3/1/3/PDF(23)/2020-HRD-1 awarded to Vandana. The work in APS lab is supported by NII core grants from DBT, Govt of India. Gene knockout work was partly supported by SERB grant (EMR/2015/001546), Govt. of India, sanctioned to APS.