RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1

Area of Science:

• Immunology
• Parasitology
• Molecular Biology

Background:

• Natural killer (NK) cells are crucial for host defense, utilizing activating and inhibitory immune receptors to distinguish self from non-self.
• Killer immunoglobulin-like receptors (KIRs) are key immune receptors, often existing in inhibitory and activating pairs with similar ligand-binding domains.
• Plasmodium falciparum repetitive interspersed family (RIFIN) proteins can inhibit NK cell activity by binding to inhibitory KIRs, aiding parasite evasion.

Purpose of the Study:

• To identify pathogen-derived ligands for human activating immune receptors.
• To investigate the interaction of RIFIN proteins with both inhibitory and activating KIRs.
• To explore the potential of targeting these interactions for malaria control.

Main Methods:

• Biochemical assays to determine RIFIN-KIR binding affinities.
• Structural biology to elucidate RIFIN-KIR binding mechanisms.
• Analysis of RIFINs in field-isolated malaria strains.

Main Results:

• Identified RIFINs that bind strongly to the inhibitory KIR2DL1, suppressing NK cell activation.
• Demonstrated that these RIFINs also bind to the activating KIR2DS1, activating NK cells.
• Confirmed the presence of these RIFINs in diverse geographical isolates of Plasmodium falciparum.

Conclusions:

• Pathogen-derived RIFINs can modulate NK cell activity through both inhibitory and activating KIRs.
• This dual interaction mechanism highlights a novel immune evasion strategy by malaria parasites.
• Targeting RIFIN-KIR interactions, particularly with activating KIRs, presents a potential therapeutic avenue for malaria.