Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection.
Gregory M MartinJonathan L TorreTossapol PholchareeDavid OyenYevel Flores-GarciaGrace GibsonRe'em MoskovitzNathan BeutlerDiana D JungJeffrey CoppsWen-Hsin LeeGonzalo Gonzalez-PaezDaniel E EmerlingRandall S MacGillEmily LockeC Richter KingFidel ZavalaIan A WilsonAndrew B WardPublished in: Nature communications (2023)
The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies and highlight key features underlying the potent protection of this antibody family.
Keyphrases
- plasmodium falciparum
- electron microscopy
- immune response
- anti inflammatory
- high resolution
- copy number
- gene expression
- machine learning
- electronic health record
- oxidative stress
- small molecule
- dendritic cells
- amino acid
- endothelial cells
- transcription factor
- drug induced
- protein protein
- dna methylation
- deep learning
- dna binding