title: Dengue encephalitis-associated immunopathology in the mouse model: Implications for vaccine developers and antigens inducer of cellular immune response.
abstract: Despite the many efforts made by the scientific community in the development of vaccine candidates against dengue virus (DENV), no vaccine has been licensed up to date. Although the immunopathogenesis associated to the disease is a key factor to take into account by vaccine developers, the lack of animal models that reproduce the clinical signs of the disease has hampered the vaccine progress. Non-human primates support viral replication, but they are very expensive and do not show signs of disease. Immunocompromised mice develop viremia and some signs of the disease; however, they are not valuable for vaccine testing. Nowadays, immunocompetent mice are the most used model to evaluate the immunogenicity of vaccine candidates. These animals are resistant to DENV infection; therefore, the intracranial inoculation with neuroadapted virus, which provokes viral encephalitis, represents an alternative to evaluate the protective capacity of vaccine candidates. Previous results have demonstrated the crucial role of cellular immune response in the protection induced by the virus and vaccine candidates in this mouse encephalitis model. However, in the present work we are proposing that the magnitude of the cell-mediated immunity and the inflammatory response generated by the vaccine can modulate the survival rate after viral challenge. We observed that the intracranial challenge of naïve mice with DENV-2 induces the recruitment of immune cells that contribute to the reduction of viral load, but does not increase the survival rate. On the contrary, animals treated with cyclophosphamide, an immunosuppressive drug that affects proliferating lymphocytes, had a higher viral load but a better survival rate than untreated animals. These results suggest that the immune system is playing an immunopathogenic role in this model and the survival rate may not be a suitable endpoint in the evaluation of vaccine candidates based on antigens that induce a strong cellular immune response.
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Marcos
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba.
authors.forename: Laura
authors.initials: L
authors.lastname: Lazo
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba. Electronic address: lazaro.gil@cigb.edu.cu.
authors.forename: Lázaro
authors.initials: L
authors.lastname: Gil
authors.affiliation: PAHO/WHO Collaborating Center for the Study of Dengue and Its Vector, Department of Virology, Pedro Kourí Tropical Medicine Institute (IPK), P.O. Box 601, Havana, Cuba.
authors.forename: Alienys
authors.initials: A
authors.lastname: Izquierdo
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba.
authors.forename: Edith
authors.initials: E
authors.lastname: Suzarte
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba.
authors.forename: Iris
authors.initials: I
authors.lastname: Valdés
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba.
authors.forename: Aracelys
authors.initials: A
authors.lastname: Blanco
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba.
authors.forename: Julio
authors.initials: J
authors.lastname: Ancizar
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba.
authors.forename: José Suárez
authors.initials: JS
authors.lastname: Alba
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba.
authors.forename: Yusleydis de la C
authors.initials: Yde L
authors.lastname: Pérez
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba.
authors.forename: Karen
authors.initials: K
authors.lastname: Cobas
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba.
authors.forename: Yaremis
authors.initials: Y
authors.lastname: Romero
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Guillén
authors.affiliation: PAHO/WHO Collaborating Center for the Study of Dengue and Its Vector, Department of Virology, Pedro Kourí Tropical Medicine Institute (IPK), P.O. Box 601, Havana, Cuba.
authors.forename: María G
authors.initials: MG
authors.lastname: Guzmán
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB) Avenue 31, P.O. Box 6162, Havana 6, 10 600, Cuba. Electronic address: lisset.hermida@cigb.edu.cu.
authors.forename: Lisset
authors.initials: L
authors.lastname: Hermida
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003520:Cyclophosphamide / Q000627:therapeutic use*; D003715:Dengue / Q000276:immunology*; D053059:Dengue Vaccines / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000276:immunology*; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007121:Immunocompetence; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D014709:Vero Cells; D019562:Viral Load
chemical_list: D053059:Dengue Vaccines; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide
keywords: Animal model; Dengue; Encephalitis; Mouse; Vaccine