Co-chaperone involvement in knob biogenesis implicates host-derived chaperones in malaria virulence

Area of Science:

• Molecular parasitology
• Cell biology
• Infectious diseases

Background:

• Malaria pathology stems from infected red blood cells (RBCs) adhering to endothelial cells.
• This adhesion is mediated by parasite-exported proteins, with many functions remaining unknown.
• Knob structures on RBCs are crucial for cytoadherence.

Purpose of the Study:

• To investigate the function of the exported J-domain protein PFA66 in malaria pathogenesis.
• To understand PFA66's role in host cell modification and cytoadherence.
• To identify PFA66's interacting partners in the host cell.

Main Methods:

• Gene inactivation of PFA66 in malaria parasites.
• Analysis of host cell morphology, surface knob structure, and PfEMP1 presentation.
• Complementation assays to restore PFA66 function.
• ATPase assays to study protein interactions.

Main Results:

• Parasites lacking PFA66 showed defects in host cell modification, including aberrant knobs and disrupted PfEMP1 presentation.
• Cytoadherence was abolished in PFA66-deficient parasites, even with KAHRP present.
• Complementation restored wild-type phenotype, indicating the J-domain's importance.
• PFA66 interacts with host HSP70 to facilitate host cell modification.

Conclusions:

• PFA66 is essential for proper host cell modification and cytoadherence in malaria.
• Human HSP70 is implicated as a crucial partner for PFA66 in this process.
• PFA66 represents a novel KAHRP-independent factor for knob biogenesis.