Broad Protection against Invasive Fungal Disease from a Nanobody Targeting the Active Site of Fungal β-1,3-Glucanosyltransferases

Invasive fungal disease accounts for about 3.8 million deaths annually, an unacceptable rate that urgently prompts the discovery of new knowledge-driven treatments. We report the use of camelid single-domain nanobodies (Nbs) against fungal β-1,3-glucanosyltransferases (Gel) involved in β-1,3-glucan...

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Detalles Bibliográficos
Autores: Redrado-Hernández, Sergio, Macías-León, Javier, Castro-López, Jorge, Belén Sanz, Ana, Dolader, Elena, Arias, Maykel, González-Ramírez, Andrés Manuel, Sánchez-Navarro, David, Petryk, Yuliya, Farkaš, Vladimír, Vincke, Cécile, Muyldermans, Serge, Garcia-Barbazan, Irene, Del Agua, Celia, Zaragoza, Oscar, Arroyo, Javier, Pardo, Julián, Gálvez, Eva M, Hurtado-Guerrero, Ramon
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/25091
Acceso en línea:https://hdl.handle.net/20.500.12105/25091
Access Level:acceso abierto
Palabra clave:Glucanosyltransferases
Cell wall
Invasive fungal infections
Nanobodies
Transglycosylases
Animals
Antifungal Agents
Aspergillus fumigatus
Catalytic Domain
Cryptococcus neoformans
Glucan Endo-1,3-beta-D-Glucosidase
Mice
Single-Domain Antibodies
Descripción
Sumario:Invasive fungal disease accounts for about 3.8 million deaths annually, an unacceptable rate that urgently prompts the discovery of new knowledge-driven treatments. We report the use of camelid single-domain nanobodies (Nbs) against fungal β-1,3-glucanosyltransferases (Gel) involved in β-1,3-glucan transglycosylation. Crystal structures of two Nbs with Gel4 from Aspergillus fumigatus revealed binding to a dissimilar CBM43 domain and a highly conserved catalytic domain across fungal species, respectively. Anti-Gel4 active site Nb3 showed significant antifungal efficacy in vitro and in vivo prophylactically and therapeutically against different A. fumigatus and Cryptococcus neoformans isolates, reducing the fungal burden and disease severity, thus significantly improving immunocompromised animal survival. Notably, C. deneoformans (serotype D) strains were more susceptible to Nb3 and genetic Gel deletion than C. neoformans (serotype A) strains, indicating a key role for β-1,3-glucan remodelling in C. deneoformans survival. These findings add new insight about the role of β-1,3-glucan in fungal biology and demonstrate the potential of nanobodies in targeting fungal enzymes to combat invasive fungal diseases.

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