Evolutionarily distant I domains can functionally replace the essential ligand-binding domain of Plasmodium TRAP

Area of Science:

• Parasitology
• Molecular Biology
• Cell Biology

Background:

• Inserted (I) domains are key ligand-binding regions in adhesins, facilitating cell adhesion and migration across eukaryotes.
• Examples include integrin heterodimers in animals and single-subunit proteins like TRAP in Plasmodium and MIC2 in Toxoplasma.

Purpose of the Study:

• To investigate the essentiality of the TRAP I domain for Plasmodium sporozoite infectivity.
• To explore the functional conservation and specificity of apicomplexan I domains by cross-species domain replacement.

Main Methods:

• Genetic manipulation of the Plasmodium berghei TRAP gene to replace its I domain with I domains from Toxoplasma MIC2 or human integrin αX.
• Assessing the impact of these genetic modifications on sporozoite gliding motility, mosquito salivary gland invasion, and mammalian host infection (liver and transmission stages).

Main Results:

• The TRAP I domain is indispensable for sporozoite gliding motility, salivary gland invasion, and successful mouse infection.
• Replacing the TRAP I domain with the Toxoplasma MIC2 I domain fully restored tissue invasion and parasite transmission.
• Substitution with the human integrin αX I domain partially restored liver infection, indicating conserved but not identical functions.
• Mutations near the ligand-binding site impaired transmission despite enabling salivary gland invasion.

Conclusions:

• Apicomplexan parasites utilize polyspecific I domains for engaging multiple host ligands, crucial for efficient invasion of diverse tissues.
• The I domain's ability to provide traction for host cell traversal is a conserved mechanism for parasite dissemination across phyla.
• Understanding I domain function offers potential targets for novel anti-parasitic strategies.