Abstract

Plasmodium-exported proteins bind with membrane receptors of host red blood cell to play the canonical role in erythrocyte invasion. While their potential to interact with immune cell receptors and orchestrate inflammatory responses remains largely unexplored. Among these proteins, tryptophan-rich antigens (TRAgs) participate in invading erythrocytes and demonstrate strong immunogenicity in murine malaria models. Here, we demonstrate that Plasmodium yoelii (Py) TRAg7 interacts with the macrophage receptor cluster of differentiation 71 (CD71) and activates nuclear factor kappa B p65 signaling pathway, which promoted the production of proinflammatory factors. Consistently, genetic deletion of TRAg7 led to decreased parasitemia, reduced inflammation, and improved host survival. Collectively, these findings reveal that exported proteins drive the inflammatory response by binding to macrophage receptor, expanding the current knowledge of the biological effects of malaria parasite-host interaction beyond erythrocyte invasion. This study offers a conceptual framework for better understanding malaria pathogenesis and potential therapeutic intervention strategies.