Cytotoxicity of human antibodies targeting the circumsporozoite protein is amplified by 3D substrate and correlates with protection
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
Human monoclonal antibodies (hmAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on the sporozoite surface are a promising tool for preventing malaria infection. However, their mechanisms of protection remain unclear. Here, using 13 distinctive PfCSP hmAbs, we provide a comprehensive view of how PfCSP hmAbs neutralize sporozoites in host tissues. Sporozoites are most vulnerable to hmAb-mediated neutralization in the skin. However, rare but potent hmAbs additionally neutralize sporozoites in the blood and liver. Efficient protection in tissues mainly associates with high-affinity and high-cytotoxicity hmAbs inducing rapid parasite loss-of-fitness in the absence of complement and host cells in vitro. A 3D-substrate assay greatly enhances hmAb cytotoxicity and mimics the skin-dependent protection, indicating that the physical stress imposed on motile sporozoites by the skin is crucial for unfolding the protective potential of hmAbs. This functional 3D cytotoxicity assay can thus be useful for downselecting potent anti-PfCSP hmAbs and vaccines.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:42 |
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| Enthalten in: |
Cell reports - 42(2023), 7 vom: 25. Juli, Seite 112681 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Aguirre-Botero, Manuela C [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 31.07.2023 Date Revised 05.09.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.celrep.2023.112681 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM358912458 |
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| 100 | 1 | |a Aguirre-Botero, Manuela C |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Cytotoxicity of human antibodies targeting the circumsporozoite protein is amplified by 3D substrate and correlates with protection |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 31.07.2023 | ||
| 500 | |a Date Revised 05.09.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Human monoclonal antibodies (hmAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on the sporozoite surface are a promising tool for preventing malaria infection. However, their mechanisms of protection remain unclear. Here, using 13 distinctive PfCSP hmAbs, we provide a comprehensive view of how PfCSP hmAbs neutralize sporozoites in host tissues. Sporozoites are most vulnerable to hmAb-mediated neutralization in the skin. However, rare but potent hmAbs additionally neutralize sporozoites in the blood and liver. Efficient protection in tissues mainly associates with high-affinity and high-cytotoxicity hmAbs inducing rapid parasite loss-of-fitness in the absence of complement and host cells in vitro. A 3D-substrate assay greatly enhances hmAb cytotoxicity and mimics the skin-dependent protection, indicating that the physical stress imposed on motile sporozoites by the skin is crucial for unfolding the protective potential of hmAbs. This functional 3D cytotoxicity assay can thus be useful for downselecting potent anti-PfCSP hmAbs and vaccines | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CP: Immunology | |
| 650 | 4 | |a antibody | |
| 650 | 4 | |a cell traversal | |
| 650 | 4 | |a cytotoxicity | |
| 650 | 4 | |a humoral immunity | |
| 650 | 4 | |a malaria | |
| 650 | 4 | |a matrigel | |
| 650 | 4 | |a motility | |
| 650 | 4 | |a skin | |
| 650 | 4 | |a sporozoite | |
| 650 | 7 | |a Malaria Vaccines |2 NLM | |
| 650 | 7 | |a Protozoan Proteins |2 NLM | |
| 650 | 7 | |a Immunoglobulins |2 NLM | |
| 700 | 1 | |a Wang, Lawrence T |e verfasserin |4 aut | |
| 700 | 1 | |a Formaglio, Pauline |e verfasserin |4 aut | |
| 700 | 1 | |a Aliprandini, Eduardo |e verfasserin |4 aut | |
| 700 | 1 | |a Thiberge, Jean-Michel |e verfasserin |4 aut | |
| 700 | 1 | |a Schön, Arne |e verfasserin |4 aut | |
| 700 | 1 | |a Flores-Garcia, Yevel |e verfasserin |4 aut | |
| 700 | 1 | |a Mathis-Torres, Shamika |e verfasserin |4 aut | |
| 700 | 1 | |a Flynn, Barbara J |e verfasserin |4 aut | |
| 700 | 1 | |a da Silva Pereira, Lais |e verfasserin |4 aut | |
| 700 | 1 | |a Le Duff, Yann |e verfasserin |4 aut | |
| 700 | 1 | |a Hurley, Mathew |e verfasserin |4 aut | |
| 700 | 1 | |a Nacer, Adéla |e verfasserin |4 aut | |
| 700 | 1 | |a Bowyer, Paul W |e verfasserin |4 aut | |
| 700 | 1 | |a Zavala, Fidel |e verfasserin |4 aut | |
| 700 | 1 | |a Idris, Azza H |e verfasserin |4 aut | |
| 700 | 1 | |a Francica, Joseph R |e verfasserin |4 aut | |
| 700 | 1 | |a Seder, Robert A |e verfasserin |4 aut | |
| 700 | 1 | |a Amino, Rogerio |e verfasserin |4 aut | |
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