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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 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.
Acknowledgments
Authors express sincere thanks to Dr Soumyananda Chakraborty for critically reviewing the MS. We thank Dr. Amit Sharma and his student Ms Swati Gupta for providing the Artemisinin resistant strain, C580Y. We are also thankful to Dr. Bhumika Kumar, (ICMR-NIMR), for providing the PfMCA-3 clone. We are grateful to Dr. Afshana Quadiri, Dr. Mohammad Kashif, Dr. Rahul, Renuka, for their extended support in terms of providing fruitful suggestions in the Manuscript. We thank the transport department of ICMR-NIMR for its timely providing office vehicle for performing experiments in collaborative Institutes. Also, we thank Mr Kuwarjeet, Mr Devesh Mishra, and Mr. Bhanu Arya, Mr.Punnet and Mr.Ramakant for their technical assistance in completing this work. Vandana would like to acknowledge Indian Council of Medical Research (ICMR) for the financial support. The present Manuscript was approved by the publication committee (No.RIC-23/2021) of ICMR-National Institute of Malaria Research (ICMR-NIMR), New Delhi.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Author contributions
Vandana and KCP developed the project, designed and optimized the experiments, interpreted the data, and wrote the Manuscript; Vandana, Inderjeet and APS generated the MCA-2 knockout and performed the animal's related experiments. Vandana, OPS and KMNP optimized the in vitro parasite culture experiments, optimization parasite artificial blood feeding experiments and data analysis. GDS and DSR involved in designing and synthesis of the chemical compounds C-532 and C-533. RKD critically review the MS. All the authors approved and reviewed the final version of the Manuscript.