TY - JOUR
T1 - Evaluation of the safety and adjuvant effect of a detoxified listeriolysin O mutant on the humoral response to dengue virus antigens
AU - Hernández-Flores, K. G.
AU - Calderón-Garcidueñas, A. L.
AU - Mellado-Sánchez, G.
AU - Ruiz-Ramos, R.
AU - Sánchez-Vargas, L. A.
AU - Thomas-Dupont, P.
AU - Izaguirre-Hernández, I. Y.
AU - Téllez-Sosa, J.
AU - Martínez-Barnetche, J.
AU - Wood, L.
AU - Paterson, Y.
AU - Cedillo-Barrón, L.
AU - López-Franco, O.
AU - Vivanco-Cid, Héctor
N1 - Publisher Copyright:
© 2016 British Society for Immunology, Clinical and Experimental Immunology.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
KW - Adjuvant
KW - Cholesterol
KW - Dengue
KW - Listeriolysin O
UR - http://www.scopus.com/inward/record.url?scp=85010400057&partnerID=8YFLogxK
U2 - 10.1111/cei.12906
DO - 10.1111/cei.12906
M3 - Artículo
C2 - 27886660
SN - 0009-9104
VL - 188
SP - 109
EP - 126
JO - Clinical and Experimental Immunology
JF - Clinical and Experimental Immunology
IS - 1
ER -