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"A long-standing question in the field of severe malaria has remained for decades: Do people living in regions with continuous malaria transmission develop specialized antibodies against the parasite and its many strains? The answer is yes, as recently discovered through a collaborative effort among researchers ...
The researchers found that broadly neutralizing antibodies (bnAbs)—specialized immune molecules—recognize and block a specific site of the PfEMP1 protein, which plays a critical role in the malaria parasite’s red blood cell stage. That specific key site of PfEMP1 represents a critical vulnerability of the parasite, as it cannot be altered without compromising the parasite’s ability to bind onto host cells. PfEMP1 works by attaching to EPCR, a receptor that allows it to adhere to the host cell surface and avoid being detected and cleared by the spleen—a necessary step in the parasite’s survival and development of severe malaria. Therefore, antibodies targeting this site effectively neutralize PfEMP1’s binding to EPCR and reduces the parasite’s virulence. ..."
From the abstract:
"Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels. This process is mediated by the polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins of the parasite. A subset of PfEMP1 variants that bind to human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here we describe two broadly reactive and inhibitory human monoclonal antibodies to CIDRα1. The antibodies isolated from two different individuals exhibited similar and consistent EPCR-binding inhibition of diverse CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins, as well as parasite sequestration in bioengineered 3D human brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with three different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies are likely to represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria."
Broadly inhibitory antibodies to severe malaria virulence proteins (no public access)
Cryo-EM structures of broadly neutralizing antibodies (pink/tan) targeting the key site (red/orange) of PfEMP1 protein (blue).
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