comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum
Roth A., Maher SP., Conway AJ., Ubalee R., Chaumeau V., Andolina C., Kaba SA., Vantaux A., Bakowski MA., Thomson-Luque R., Adapa SR., Singh N., Barnes SJ., Cooper CA., Rouillier M., McNamara CW., Mikolajczak SA., Sather N., Witkowski B., Campo B., Kappe SHI., Lanar DE., Nosten F., Davidson S., Jiang RHY., Kyle DE., Adams JH.
AbstractMalaria liver stages represent an ideal therapeutic target with a bottleneck in parasite load and reduced clinical symptoms; however, current in vitro pre-erythrocytic (PE) models forPlasmodium vivaxandP.falciparumlack the efficiency necessary for rapid identification and effective evaluation of new vaccines and drugs, especially targeting late liver-stage development and hypnozoites. Herein we report the development of a 384-well plate culture system using commercially available materials, including cryopreserved primary human hepatocytes. Hepatocyte physiology is maintained for at least 30 days and supports development ofP.vivaxhypnozoites and complete maturation ofP.vivaxandP.falciparumschizonts. Our multimodal analysis in antimalarial therapeutic research identifies important PE inhibition mechanisms: immune antibodies against sporozoite surface proteins functionally inhibit liver stage development and ion homeostasis is essential for schizont and hypnozoite viability. This model can be implemented in laboratories in disease-endemic areas to accelerate vaccine and drug discovery research.