Asparagine requirement in Plasmodium berghei as a target to prevent malaria transmission and liver infections

Viswanathan A. Nagaraj (), Dhanunjay Mukhi, Vinayagam Sathishkumar, Pradeep A. Subramani, Susanta K. Ghosh, Rajeev R. Pandey, Manjunatha C. Shetty and Govindarajan Padmanaban
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Viswanathan A. Nagaraj: Indian Institute of Science
Dhanunjay Mukhi: Indian Institute of Science
Vinayagam Sathishkumar: Centre for Infectious Disease Research, Indian Institute of Science
Pradeep A. Subramani: National Institute of Malaria Research (Field Unit)
Susanta K. Ghosh: National Institute of Malaria Research (Field Unit)
Rajeev R. Pandey: Indian Institute of Science
Manjunatha C. Shetty: Centre for Infectious Disease Research, Indian Institute of Science
Govindarajan Padmanaban: Indian Institute of Science

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract The proteins of Plasmodium, the malaria parasite, are strikingly rich in asparagine. Plasmodium depends primarily on host haemoglobin degradation for amino acids and has a rudimentary pathway for amino acid biosynthesis, but retains a gene encoding asparagine synthetase (AS). Here we show that deletion of AS in Plasmodium berghei (Pb) delays the asexual- and liver-stage development with substantial reduction in the formation of ookinetes, oocysts and sporozoites in mosquitoes. In the absence of asparagine synthesis, extracellular asparagine supports suboptimal survival of PbAS knockout (KO) parasites. Depletion of blood asparagine levels by treating PbASKO-infected mice with asparaginase completely prevents the development of liver stages, exflagellation of male gametocytes and the subsequent formation of sexual stages. In vivo supplementation of asparagine in mice restores the exflagellation of PbASKO parasites. Thus, the parasite life cycle has an absolute requirement for asparagine, which we propose could be targeted to prevent malaria transmission and liver infections.

Date: 2015
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DOI: 10.1038/ncomms9775

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