Abstract
Elucidating the molecular mechanisms of the host-parasite interaction during red cell invasion by Plasmodium is important for developing newer antimalarial therapeutics. Recently, we have characterized a Plasmodium vivax tryptophan-rich antigen PvTRAg38, which is expressed by its merozoites, binds to host erythrocytes, and interferes with parasite growth. Interaction of this parasite ligand with the host erythrocyte occurs through its two regions present at amino acid positions 167-178 (P2) and 197-208 (P4). Each region recognizes its own erythrocyte receptor. Previously, we identified band 3 as the chymotrypsin-sensitive erythrocyte receptor for the P4 region, but the other receptor, binding to P2 region, remained unknown. Here, we have identified basigin as the second erythrocyte receptor for PvTRAg38, which is resistant to chymotrypsin. The specificity of interaction between PvTRAg38 and basigin was confirmed by direct interaction where basigin was specifically recognized by P2 and not by the P4 region of this parasite ligand. Interaction between P2 and basigin is stabilized through multiple amino acid residues, but Gly-171 and Leu-175 of P2 were more critical. These two amino acids were also critical for parasite growth. Synthetic peptides P2 and P4 of PvTRAg38 interfered with the parasite growth independently but had an additive effect if combined together indicating involvement of both the receptors during red cell invasion. In conclusion, PvTRAg38 binds to two erythrocyte receptors basigin and band 3 through P2 and P4 regions, respectively, to facilitate parasite growth. This advancement in our knowledge on molecular mechanisms of host-parasite interaction can be exploited to develop therapeutics against P. vivax malaria.
Highlights
Elucidating the molecular mechanisms of the host-parasite interaction during red cell invasion by Plasmodium is important for developing newer antimalarial therapeutics
Interacting Erythrocyte Protein Partners for PvTRAg38 —Previous studies have shown that the parasite ligand PvTRAg38 interacts with two erythrocyte receptors, where one of them was sensitive to chymotrypsin [14]
As it is known that PvTRAg38 recognizes two erythrocyte receptors [14] and peptide P4 binds to one of them, identified as band 3 [19], we investigated here whether peptide P2 of this parasite ligand binds to the above-identified basigin as second erythrocyte receptor
Summary
23 8 7 6 4 3 2 shown to recognize a different receptor for invasion in Duffy null erythrocytes [12]. We have reported that several P. vivax tryptophan-rich antigens (PvTRAgs) belonging to the pv-fam-a family were highly immunogenic in humans, have conserved sequences in parasite population, and bind to host erythrocytes through two receptors (14 –17). We have been able to define two erythrocyte-binding regions, P2 (at amino acid position 167–178) and P4 (at amino acid position 198 –208), of this parasite ligand that interact with two different erythrocyte receptors. Results of this study indicate that this chymotrypsin-resistant erythrocyte receptor for PvTRAg38 recognized by its P2 region is basigin. Both P2 and P4 peptides interfere with parasite growth, signifying the involvement of both receptors, basigin and band 3, in red cell invasion
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