The sexual forms of Plasmodium falciparum (Pf), the causative agent of malaria, are transmitted from humans to mosquitoes, enabling the parasite to spread. It is well established that antibodies (Ac) can efficiently block parasite transmission.
To identify the targets of these antibodies, the Complement, antibodies and infectious disease Group developed a high-throughput screening method : after non-specific activation of memory B cells from blood samples, the antibodies produced were selected for their ability to bind to the sexual stages of Pf. This approach led to the isolation of fourteen mAbs targeting various Pf proteins.
One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle, including asexual blood stages. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions.
Until now, this recognition mode had only been observed for repetitive motifs of different natures of the PfCSP protein, from the pre-erythrocytic stage of Pf. The results therefore suggest that this mode of recognition by Ac may be characteristic of repetitive motifs in general. Furthermore, cross-recognition by Ac of these motifs found in proteins expressed at successive stages of the parasite could promote Pf’s escape from protective humoral responses via epitopic masking mechanisms.
Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross stage recognition of glutamate-rich repeats. Amen A, Yoo R, Fabra-García A, Bolscher J, Stone WJR, Bally I, Dergan-Dylon S, Kucharska I, de Jong RM, de Bruijni M, Bousema T, King CR, MacGill RS, Sauerwein RW, Julien JP, Poignard P, Jore MM. eLife https://doi.org/10.7554/eLife.97865.2.sa3
Contact : Pascal Poignard (IBS/Complement, antibodies and infectious disease Group)