Complete Plasmodium falciparum liver-stage development in liver-chimeric mice

Area of Science:

• Malariology
• Infectious Diseases
• Animal Models

Background:

• Plasmodium falciparum causes severe human malaria, with its initial liver-stage (LS) development being critical but difficult to study in vivo.
• Existing in vitro models do not accurately replicate the conditions for parasite LS development.

Purpose of the Study:

• To establish a robust in vivo model for studying Plasmodium falciparum liver-stage development in humans.
• To investigate previously uncharacterized protein expression during the LS of P. falciparum.

Main Methods:

• Utilized fumarylacetoacetate hydrolase-deficient (Fah-/-, Rag2-/-, Il2rg-/-) mice engrafted with human hepatocytes (FRG huHep mice).
• Infected FRG huHep mice with P. falciparum to observe LS development and protein expression.
• Developed a secondary model with FRG mice backcrossed to NOD, repopulated with human hepatocytes and red blood cells, to study LS-to-blood-stage transition.

Main Results:

• FRG huHep mice supported vigorous and quantifiable P. falciparum LS development, with complete maturation observed around 7 days post-infection.
• Observed novel expression of proteins like P. falciparum translocon of exported proteins 150 (PTEX150) and exported protein-2 (EXP-2) in LS schizonts.
• Demonstrated reproducible transition from LS to blood-stage infection in the secondary model.

Conclusions:

• The FRG huHep mouse model provides a relevant platform for in vivo study of human malaria liver-stage development.
• This model facilitates the observation of parasite protein export machinery and merozoite formation.
• The developed models are valuable tools for studying the complete lifecycle of P. falciparum, including the critical transition to blood-stage infection.