scholarly journals Correction for Oyen et al., Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein

2018 ◽  
Vol 115 (25) ◽  
pp. E5838-E5839 ◽  
Keyword(s):  
Plasmodium Falciparum ◽  
Circumsporozoite Protein ◽  
Structural Basis ◽  
Antibody Recognition

scholarly journals Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Iga Kucharska ◽  
Lamia Hossain ◽  
Danton Ivanochko ◽  
Qiren Yang ◽  
John L Rubinstein ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Molecular Basis ◽  
Parasite Infection ◽  
Circumsporozoite Protein ◽  
Structural Basis ◽  
Structural Studies ◽  
Repeat Region ◽  
Antibody Recognition ◽  
Peptide Conformations ◽  
Dynamics Simulations

Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions, and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines.

scholarly journals Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein

2017 ◽  
Vol 114 (48) ◽  
pp. E10438-E10445 ◽  
Author(s):  
David Oyen ◽  
Jonathan L. Torres ◽  
Ulrike Wille-Reece ◽  
Christian F. Ockenhouse ◽  
Daniel Emerling ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Vaccine ◽  
Acquired Resistance ◽  
Circumsporozoite Protein ◽  
Phase Iii ◽  
Structural Basis ◽  
Parasite Development ◽  
Type I ◽  
Binding Modes

Acquired resistance against antimalarial drugs has further increased the need for an effective malaria vaccine. The current leading candidate, RTS,S, is a recombinant circumsporozoite protein (CSP)-based vaccine against Plasmodium falciparum that contains 19 NANP repeats followed by a thrombospondin repeat domain. Although RTS,S has undergone extensive clinical testing and has progressed through phase III clinical trials, continued efforts are underway to enhance its efficacy and duration of protection. Here, we determined that two monoclonal antibodies (mAbs 311 and 317), isolated from a recent controlled human malaria infection trial exploring a delayed fractional dose, inhibit parasite development in vivo by at least 97%. Crystal structures of antibody fragments (Fabs) 311 and 317 with an (NPNA)3 peptide illustrate their different binding modes. Notwithstanding, one and three of the three NPNA repeats adopt similar well-defined type I β-turns with Fab311 and Fab317, respectively. Furthermore, to explore antibody binding in the context of P. falciparum CSP, we used negative-stain electron microscopy on a recombinant shortened CSP (rsCSP) construct saturated with Fabs. Both complexes display a compact rsCSP with multiple Fabs bound, with the rsCSP–Fab311 complex forming a highly organized helical structure. Together, these structural insights may aid in the design of a next-generation malaria vaccine.

scholarly journals Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats

2021 ◽  
Author(s):  
Iga Kucharska ◽  
Lamia Hossain ◽  
Danton Ivanochko ◽  
Qiren Yang ◽  
John L Rubinstein ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Molecular Basis ◽  
Parasite Infection ◽  
Circumsporozoite Protein ◽  
Structural Basis ◽  
Structural Studies ◽  
Repeat Region ◽  
Antibody Recognition ◽  
Peptide Conformations ◽  
Dynamics Simulations

Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions, and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines.

scholarly journals Diverse Antibody Responses to Conserved Structural Motifs in Plasmodium falciparum Circumsporozoite Protein

2020 ◽  
Vol 432 (4) ◽  
pp. 1048-1063 ◽  
Author(s):  
Tossapol Pholcharee ◽  
David Oyen ◽  
Jonathan L. Torres ◽  
Yevel Flores-Garcia ◽  
Gregory M. Martin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antibody Responses ◽  
Circumsporozoite Protein ◽  
Structural Motifs

scholarly journals In vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Merricka C. Livingstone ◽  
Alexis A. Bitzer ◽  
Alish Giri ◽  
Kun Luo ◽  
Rajeshwer S. Sankhala ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Monoclonal Antibodies ◽  
Disease Burden ◽  
Vaccine Candidate ◽  
Specific Binding ◽  
Circumsporozoite Protein ◽  
Target Epitope ◽  
Selection Of

AbstractPlasmodium falciparum malaria contributes to a significant global disease burden. Circumsporozoite protein (CSP), the most abundant sporozoite stage antigen, is a prime vaccine candidate. Inhibitory monoclonal antibodies (mAbs) against CSP map to either a short junctional sequence or the central (NPNA)n repeat region. We compared in vitro and in vivo activities of six CSP-specific mAbs derived from human recipients of a recombinant CSP vaccine RTS,S/AS01 (mAbs 317 and 311); an irradiated whole sporozoite vaccine PfSPZ (mAbs CIS43 and MGG4); or individuals exposed to malaria (mAbs 580 and 663). RTS,S mAb 317 that specifically binds the (NPNA)n epitope, had the highest affinity and it elicited the best sterile protection in mice. The most potent inhibitor of sporozoite invasion in vitro was mAb CIS43 which shows dual-specific binding to the junctional sequence and (NPNA)n. In vivo mouse protection was associated with the mAb reactivity to the NANPx6 peptide, the in vitro inhibition of sporozoite invasion activity, and kinetic parameters measured using intact mAbs or their Fab fragments. Buried surface area between mAb and its target epitope was also associated with in vivo protection. Association and disconnects between in vitro and in vivo readouts has important implications for the design and down-selection of the next generation of CSP based interventions.

scholarly journals Comparative population structure of Plasmodium falciparum circumsporozoite protein NANP repeat lengths in Lilongwe, Malawi

2013 ◽  
Vol 3 (1) ◽  
Author(s):  
Natalie M. Bowman ◽  
Seth Congdon ◽  
Tisungane Mvalo ◽  
Jaymin C. Patel ◽  
Veronica Escamilla ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Population Structure ◽  
Circumsporozoite Protein ◽  
Comparative Population

Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors

Parasitology ◽  
2005 ◽  
Vol 130 (3) ◽  
pp. 249-259 ◽  
Author(s):  
Y. YUTHAVONG ◽  
J. YUVANIYAMA ◽  
P. CHITNUMSUB ◽  
J. VANICHTANANKUL ◽  
S. CHUSACULTANACHAI ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Thymidylate Synthase ◽  
Structural Basis ◽  
Antifolate Resistance

scholarly journals How to induce protective humoral immunity against Plasmodium falciparum circumsporozoite protein

2022 ◽  
Vol 219 (2) ◽  
Author(s):  
Ilka Wahl ◽  
Hedda Wardemann
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Vaccine Efficacy ◽  
Circumsporozoite Protein ◽  
Surface Proteins ◽  
Humoral Immune ◽  
Cell Responses ◽  
Humoral Immune Responses ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum

The induction of protective humoral immune responses against sporozoite surface proteins of the human parasite Plasmodium falciparum (Pf) is a prime goal in the development of a preerythrocytic malaria vaccine. The most promising antibody target is circumsporozoite protein (CSP). Although PfCSP induces strong humoral immune responses upon vaccination, vaccine efficacy is overall limited and not durable. Here, we review recent efforts to gain a better molecular and cellular understanding of anti-PfCSP B cell responses in humans and discuss ways to overcome limitations in the induction of stable titers of high-affinity antibodies that might help to increase vaccine efficacy and promote long-lived protection.

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