Last Updated: 06/11/2024
Elucidating mechanisms of cell death in Plasmodium vivax-infected hepatocytes
Objectives
This project aims to elucidate host regulators of developing and dormant stages of P. vivax. The proposal sets to characterize cell death signaling in P. vivax-infected hepatocytets over a time course in vitro and in vivo, and to determine how inhibiting or promoting this signaling using chemical and knockdown approaches alters initial liver-stage infection and reactivation of hypnozoites.
This work addresses the FY23 PRMRP portfolio category of Infectious Diseases, specifically the FY23 PRMRP topic area of Malaria and its strategic goal for foundational studies to elucidate and prevent long-term complications following infections. One of the major hurdles to malaria eradication is the ability of Plasmodium vivax to form dormant liver-stages called hypnozoites, which reside within the liver for weeks to months before being reactivated and causing relapsing infection. Due to difficulties in culturing the parasite, little is known about the biology of this stage, particularly for hypnozoite maintenance and reactivation. The hypothesis is that programmed cell death signaling within the host hepatocyte regulates both initial infection with P. vivax and reactivation of dormant hypnozoites. This project will take advantage of advances in long-term in vitro systems, the human liver-chimeric mouse model, and recently developed cryopreserved P. vivax sporozoites to investigate the role of apoptotic and ferroptotic cell death signaling in regulating infection. It is anticipated that this will help identify novel host regulators of P. vivax liver-stage infection which will enhance current understanding of infection dynamics and could inform the development of host-targeted therapeutics. Additionally, because how infected cells die can inform subsequent immunity, our understanding could lead to better ways to ensure immunity against malaria.
Jan 2024 — Jan 2026
$393,800
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