Many pathogens evolve extensive genetic variation in virulence
proteins as a strategy to evade host immunity. This poses a significant challenge for the host to develop
broadly neutralizing antibodies. In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to elicit
antibodies to cryptic
epitopes that are not under immune pressure. We previously discovered that
antibodies to the Plasmodium vivax invasion
protein, PvDBP, cross-react with P. falciparum VAR2CSA, a distantly related
virulence factor that mediates placental
malaria. Here, we describe the molecular mechanism underlying this cross-species immunity. We identified an
epitope in subdomain 1 (
SD1) within the Duffy binding-like (DBL) domain of PvDBP that gives rise to cross-reactive
antibodies to VAR2CSA and show that human
antibodies affinity purified against a synthetic
SD1 peptide block parasite adhesion to
chondroitin sulfate A (CSA) in vitro The
epitope in
SD1 is subdominant and highly conserved in PvDBP, and in turn,
SD1 antibodies target cryptic
epitopes in P. falciparum VAR2CSA. The
epitopes in VAR2CSA recognized by vivax-derived
SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two
peptides in the DBL5ε domain of VAR2CSA that are recognized by
SD1 antibodies. Both
peptides map to regions outside the
immunodominant sites, and
antibodies to these
peptides are not elicited following immunization with VAR2CSA or natural
infection with P. falciparum in pregnancy, consistent with the cryptic nature of these target
epitopes.IMPORTANCE In this work, we describe a molecular mechanism of heterologous immunity between two distant species of Plasmodium Our results suggest a mechanism that subverts the classic parasite strategy of presenting highly polymorphic
epitopes in
surface antigens to evade immunity to that parasite. This alternative immune pathway can be exploited to protect pregnant women from falciparum placental
malaria by designing
vaccines to cryptic
epitopes that elicit broadly inhibitory
antibodies against variant parasite strains.