Evaluation of the safety and adjuvant effect of a detoxified listeriolysin O mutant on the humoral response to dengue virus antigens.

Autor: Hernández-Flores KG; Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz City, Veracruz, México.; Doctorado en Ciencias Biomédicas, Centro de Investigaciones Biomédicas, Universidad Veracruzana, Xalapa Veracruz, México., Calderón-Garcidueñas AL; Instituto de Medicina Forense, Universidad Veracruzana, Boca del Río Veracruz, México., Mellado-Sánchez G; Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz City, Veracruz, México., Ruiz-Ramos R; Instituto de Medicina Forense, Universidad Veracruzana, Boca del Río Veracruz, México., Sánchez-Vargas LA; Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz City, Veracruz, México.; Doctorado en Ciencias Biomédicas, Centro de Investigaciones Biomédicas, Universidad Veracruzana, Xalapa Veracruz, México., Thomas-Dupont P; Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz City, Veracruz, México.; Doctorado en Ciencias Biomédicas, Centro de Investigaciones Biomédicas, Universidad Veracruzana, Xalapa Veracruz, México., Izaguirre-Hernández IY; Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz City, Veracruz, México.; Doctorado en Ciencias Biomédicas, Centro de Investigaciones Biomédicas, Universidad Veracruzana, Xalapa Veracruz, México., Téllez-Sosa J; Departamento de Inmunología, Instituto Nacional de Salud Pública (INSP), Centro de Investigación Sobre Enfermedades Infecciosas (CISEI), Cuernavaca, México., Martínez-Barnetche J; Departamento de Inmunología, Instituto Nacional de Salud Pública (INSP), Centro de Investigación Sobre Enfermedades Infecciosas (CISEI), Cuernavaca, México., Wood L; Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA., Paterson Y; Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA., Cedillo-Barrón L; Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados IPN, Ciudad de México, México., López-Franco O; Centro de Estudios y Servicios en Salud. Universidad Veracruzana, Veracruz City, Veracruz, México., Vivanco-Cid H; Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz City, Veracruz, México.
Jazyk: angličtina
Zdroj: Clinical and experimental immunology [Clin Exp Immunol] 2017 Apr; Vol. 188 (1), pp. 109-126. Date of Electronic Publication: 2017 Jan 19.
DOI: 10.1111/cei.12906
Abstrakt: Listeriolysin O (LLO) has been proposed as a potential carrier or adjuvant molecule in the vaccination field. However, the cytotoxic and pro-apoptotic effects of LLO are the major limitations for this purpose. Here, we have performed a preclinical safety evaluation and characterized a new potential adjuvant application for a non-cytolytic LLO mutant (dtLLO) to enhance and modulate the immune response against the envelope (E) protein from dengue virus. In addition, we have studied the adjuvant effects of dtLLO on human immune cells and the role of membrane cholesterol for the binding and proinflammatory property of the toxoid. Our in-vivo results in the murine model confirmed that dtLLO is a safer molecule than wild-type LLO (wtLLO), with a significantly increased survival rate for mice challenged with dtLLO compared with mice challenged with wtLLO (P < 0·001). Histopathological analysis showed non-toxic effects in key target organs such as brain, heart, liver, spleen, kidney and lung after challenge with dtLLO. In vitro, dtLLO retained the capacity of binding to plasma membrane cholesterol on the surface of murine and human immune cells. Immunization of 6-8-week-old female BALB/c mice with a combination of dtLLO mixed with E protein elicited a robust specific humoral response with isotype diversification of immunoglobulin (Ig)G antibodies (IgG1 and IgG2a). Finally, we demonstrated that cholesterol and lipid raft integrity are required to induce a proinflammatory response by human cells. Taken together, these findings support a potential use of the dtLLO mutant as a safe and effective adjuvant molecule in vaccination.
(© 2016 British Society for Immunology.)
Databáze: MEDLINE
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