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

Author

Listed:
  • Manjunatha Chandana

    (Institute of Life Sciences
    Kalinga Institute of Industrial Technology)

  • Aditya Anand

    (Institute of Life Sciences
    Regional Centre for Biotechnology)

  • Sourav Ghosh

    (Institute of Life Sciences
    Regional Centre for Biotechnology)

  • Rahul Das

    (Institute of Life Sciences
    Regional Centre for Biotechnology)

  • 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)

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.

Suggested Citation

  • Manjunatha Chandana & Aditya Anand & Sourav Ghosh & Rahul Das & Subhashree Beura & Sarita Jena & Amol Ratnakar Suryawanshi & Govindarajan Padmanaban & Viswanathan Arun Nagaraj, 2022. "Malaria parasite heme biosynthesis promotes and griseofulvin protects against cerebral malaria in mice," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31431-z
    DOI: 10.1038/s41467-022-31431-z
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    References listed on IDEAS

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    1. Clare R. Harding & Saima M. Sidik & Boryana Petrova & Nina F. Gnädig & John Okombo & Alice L. Herneisen & Kurt E. Ward & Benedikt M. Markus & Elizabeth A. Boydston & David A. Fidock & Sebastian Lourid, 2020. "Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
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    Cited by:

    1. Sourav Ghosh & Rajib Kundu & Manjunatha Chandana & Rahul Das & Aditya Anand & Subhashree Beura & Ruchir Chandrakant Bobde & Vishal Jain & Sowmya Ramakant Prabhu & Prativa Kumari Behera & Akshaya Kumar, 2023. "Distinct evolution of type I glutamine synthetase in Plasmodium and its species-specific requirement," Nature Communications, Nature, vol. 14(1), pages 1-27, December.
    2. Rabindra K. Mandal & Anita Mandal & Joshua E. Denny & Ruth Namazii & Chandy C. John & Nathan W. Schmidt, 2023. "Gut Bacteroides act in a microbial consortium to cause susceptibility to severe malaria," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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