| Structural highlights
Function
RH5_PLAF7 Essential for the invasion of host erythrocytes by blood stage merozoites (PubMed:18827878, PubMed:19000690, PubMed:22080952, PubMed:25296023, PubMed:25583518, PubMed:27374406, PubMed:28186186, PubMed:28409866, PubMed:31204103). By binding P113 at the surface of the merozoite and human BSG/basigin on the erythrocyte membrane, leads to the establishment of a tight junction between the merozoite and host erythrocyte membranes (PubMed:22080952, PubMed:25296023, PubMed:25583518, PubMed:27374406, PubMed:28186186). In addition, the interaction with BSG results in BSG dimerization which triggers an increase in intracellular Ca(2+) in the erythrocyte (PubMed:27374406, PubMed:28409866). This essential step leads to a rearrangement of the erythrocyte cytoskeleton required for the merozoite invasion (PubMed:28409866).[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the leading target for next-generation vaccines against the disease-causing blood-stage of malaria. However, little is known about how human antibodies confer functional immunity against this antigen. We isolated a panel of human monoclonal antibodies (mAbs) against PfRH5 from peripheral blood B cells from vaccinees in the first clinical trial of a PfRH5-based vaccine. We identified a subset of mAbs with neutralizing activity that bind to three distinct sites and another subset of mAbs that are non-functional, or even antagonistic to neutralizing antibodies. We also identify the epitope of a novel group of non-neutralizing antibodies that significantly reduce the speed of red blood cell invasion by the merozoite, thereby potentiating the effect of all neutralizing PfRH5 antibodies as well as synergizing with antibodies targeting other malaria invasion proteins. Our results provide a roadmap for structure-guided vaccine development to maximize antibody efficacy against blood-stage malaria.
Human Antibodies that Slow Erythrocyte Invasion Potentiate Malaria-Neutralizing Antibodies.,Alanine DGW, Quinkert D, Kumarasingha R, Mehmood S, Donnellan FR, Minkah NK, Dadonaite B, Diouf A, Galaway F, Silk SE, Jamwal A, Marshall JM, Miura K, Foquet L, Elias SC, Labbe GM, Douglas AD, Jin J, Payne RO, Illingworth JJ, Pattinson DJ, Pulido D, Williams BG, de Jongh WA, Wright GJ, Kappe SHI, Robinson CV, Long CA, Crabb BS, Gilson PR, Higgins MK, Draper SJ Cell. 2019 Jun 13. pii: S0092-8674(19)30553-7. doi: 10.1016/j.cell.2019.05.025. PMID:31204103[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Rodriguez M, Lustigman S, Montero E, Oksov Y, Lobo CA. PfRH5: a novel reticulocyte-binding family homolog of plasmodium falciparum that binds to the erythrocyte, and an investigation of its receptor. PLoS One. 2008 Oct 1;3(10):e3300. PMID:18827878 doi:10.1371/journal.pone.0003300
- ↑ Baum J, Chen L, Healer J, Lopaticki S, Boyle M, Triglia T, Ehlgen F, Ralph SA, Beeson JG, Cowman AF. Reticulocyte-binding protein homologue 5 invasion of human erythrocytes by Plasmodium falciparum. Int J Parasitol. 2009 Feb;39(3):371-80. PMID:19000690 doi:10.1016/j.ijpara.2008.10.006
- ↑ Crosnier C, Bustamante LY, Bartholdson SJ, Bei AK, Theron M, Uchikawa M, Mboup S, Ndir O, Kwiatkowski DP, Duraisingh MT, Rayner JC, Wright GJ. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature. 2011 Nov 9;480(7378):534-7. PMID:22080952 doi:10.1038/nature10606
- ↑ Chen L, Xu Y, Healer J, Thompson JK, Smith BJ, Lawrence MC, Cowman AF. Crystal structure of PfRh5, an essential P. falciparum ligand for invasion of human erythrocytes. Elife. 2014 Oct 8;3:e04187. PMID:25296023 doi:10.7554/eLife.04187
- ↑ Reddy KS, Amlabu E, Pandey AK, Mitra P, Chauhan VS, Gaur D. Multiprotein complex between the GPI-anchored CyRPA with PfRH5 and PfRipr is crucial for Plasmodium falciparum erythrocyte invasion. Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1179-84. PMID:25583518 doi:10.1073/pnas.1415466112
- ↑ Volz JC, Yap A, Sisquella X, Thompson JK, Lim NT, Whitehead LW, Chen L, Lampe M, Tham WH, Wilson D, Nebl T, Marapana D, Triglia T, Wong W, Rogers KL, Cowman AF. Essential Role of the PfRh5/PfRipr/CyRPA Complex during Plasmodium falciparum Invasion of Erythrocytes. Cell Host Microbe. 2016 Jul 13;20(1):60-71. PMID:27374406 doi:10.1016/j.chom.2016.06.004
- ↑ Galaway F, Drought LG, Fala M, Cross N, Kemp AC, Rayner JC, Wright GJ. P113 is a merozoite surface protein that binds the N terminus of Plasmodium falciparum RH5. Nat Commun. 2017 Feb 10;8:14333. PMID:28186186 doi:10.1038/ncomms14333
- ↑ Aniweh Y, Gao X, Hao P, Meng W, Lai SK, Gunalan K, Chu TT, Sinha A, Lescar J, Chandramohanadas R, Li HY, Sze SK, Preiser PR. P. falciparum RH5-Basigin interaction induces changes in the cytoskeleton of the host RBC. Cell Microbiol. 2017 Sep;19(9). PMID:28409866 doi:10.1111/cmi.12747
- ↑ Alanine DGW, Quinkert D, Kumarasingha R, Mehmood S, Donnellan FR, Minkah NK, Dadonaite B, Diouf A, Galaway F, Silk SE, Jamwal A, Marshall JM, Miura K, Foquet L, Elias SC, Labbe GM, Douglas AD, Jin J, Payne RO, Illingworth JJ, Pattinson DJ, Pulido D, Williams BG, de Jongh WA, Wright GJ, Kappe SHI, Robinson CV, Long CA, Crabb BS, Gilson PR, Higgins MK, Draper SJ. Human Antibodies that Slow Erythrocyte Invasion Potentiate Malaria-Neutralizing Antibodies. Cell. 2019 Jun 13. pii: S0092-8674(19)30553-7. doi: 10.1016/j.cell.2019.05.025. PMID:31204103 doi:http://dx.doi.org/10.1016/j.cell.2019.05.025
- ↑ Alanine DGW, Quinkert D, Kumarasingha R, Mehmood S, Donnellan FR, Minkah NK, Dadonaite B, Diouf A, Galaway F, Silk SE, Jamwal A, Marshall JM, Miura K, Foquet L, Elias SC, Labbe GM, Douglas AD, Jin J, Payne RO, Illingworth JJ, Pattinson DJ, Pulido D, Williams BG, de Jongh WA, Wright GJ, Kappe SHI, Robinson CV, Long CA, Crabb BS, Gilson PR, Higgins MK, Draper SJ. Human Antibodies that Slow Erythrocyte Invasion Potentiate Malaria-Neutralizing Antibodies. Cell. 2019 Jun 13. pii: S0092-8674(19)30553-7. doi: 10.1016/j.cell.2019.05.025. PMID:31204103 doi:http://dx.doi.org/10.1016/j.cell.2019.05.025
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