Malaria parasite heme biosynthesis promotes and griseofulvin protects against cerebral malaria in mice

Manjunatha Chandana, Aditya Anand, Sourav Ghosh, Rahul Das, Subhashree Beura, Sarita Jena, Amol Ratnakar Suryawanshi, Govindarajan Padmanaban and Viswanathan Arun Nagaraj ()
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Manjunatha Chandana: Institute of Life Sciences
Aditya Anand: Institute of Life Sciences
Sourav Ghosh: Institute of Life Sciences
Rahul Das: Institute of Life Sciences
Subhashree Beura: Institute of Life Sciences
Sarita Jena: Institute of Life Sciences
Amol Ratnakar Suryawanshi: Institute of Life Sciences
Govindarajan Padmanaban: Indian Institute of Science
Viswanathan Arun Nagaraj: Institute of Life Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract Heme-biosynthetic pathway of malaria parasite is dispensable for asexual stages, but essential for mosquito and liver stages. Despite having backup mechanisms to acquire hemoglobin-heme, pathway intermediates and/or enzymes from the host, asexual parasites express heme pathway enzymes and synthesize heme. Here we show heme synthesized in asexual stages promotes cerebral pathogenesis by enhancing hemozoin formation. Hemozoin is a parasite molecule associated with inflammation, aberrant host-immune responses, disease severity and cerebral pathogenesis. The heme pathway knockout parasites synthesize less hemozoin, and mice infected with knockout parasites are protected from cerebral malaria and death due to anemia is delayed. Biosynthetic heme regulates food vacuole integrity and the food vacuoles from knockout parasites are compromised in pH, lipid unsaturation and proteins, essential for hemozoin formation. Targeting parasite heme synthesis by griseofulvin—a FDA-approved antifungal drug, prevents cerebral malaria in mice and provides an adjunct therapeutic option for cerebral and severe malaria.

Date: 2022
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DOI: 10.1038/s41467-022-31431-z

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