A subset of Plasmodium falciparum RIFINs is linked to severe malaria risk reduction and engages LILRB1 through a conserved structural motif

BACKGROUND: RIFIN proteins are key mediators of Plasmodium falciparum immune evasion through antigenic variation and inhibitory receptor interactions; however, some RIFIN variants elicit protective antibody responses in individuals with malaria. While it is not surprising that RIFINs provoke immune responses, the functional and structural basis of both the association of RIFINs with clinical outcomes and their engagement with inhibitory receptors remains a critical knowledge gap in malaria immunology. METHODS: In a systematic immunoproteomic analysis that uses protein microarrays, we profiled anti-RIFIN antibody responses in individuals with malaria and correlated these responses with disease severity. Candidate RIFINs linked to severe malaria risk reduction were identified and validated via logistic regression analyses. The functional and structural basis of these RIFIN candidates was assessed via surface plasmon resonance (SPR) binding assays and structural modelling, with mechanistic insights derived from crystallographic analyses of LILRB1-RIFIN complexes and synthetic peptide interaction studies. FINDINGS: We identified a RIFIN subset associated with a reduced risk of severe malaria. These RIFINs engage the inhibitory receptor LILRB1 through a conserved structural motif anchored by disulfide-bonded cysteines, despite overwhelming sequence diversity across the RIFIN family. LILRB1 binds both RIFINs and MHC-I ligands by overlapping interfaces, confirming that a convergent recognition strategy is exploited by the malaria pathogens and their hosts. INTERPRETATION: Our study identified a bifunctional RIFIN subset that balances clinical immunity and immune evasion through a structurally conserved LILRB1-binding motif. These findings provide a blueprint for rational intervention strategies: the motif can guide vaccine design to overcome diversity by (1) eliciting antibodies to the structurally constrained, functional site or (2) disrupting immune evasion while leaving other protective epitopes. This work improves our understanding of RIFIN biology and opens new avenues to disrupt P. falciparum severe pathogenesis and reduce the global malaria burden. FUNDING: Shanghai Natural Science Foundation (Grant No. 24ZR1473200); Bill & Melinda Gates Foundation (Grant No. INV-003421); National Key Research and Development Program of China (Grant Nos. 2018YFE0121600 and 2016YFC1202000); Special Fund for Health Research in the Public Interest (Grant No. 201202019); National Natural Science Foundation of China (Grant No. 81702032); Open Grant of the NHC Key Laboratory of Parasite and Vector Biology (National Institute of Parasitic Diseases, Chinese Center for Diseases Control and Prevention; Grant No. NHCKFKT2021-04).