The Role of Heterotypic DENV-specific CD8+T Lymphocytes in an Immunocompetent Mouse Model of Secondary Dengue Virus Infection

• Published in: EBioMedicine Vol. 20; no. C; pp. 202 - 216
• Main Authors: Talarico, Laura B., Batalle, Juan P., Byrne, Alana B., Brahamian, Jorge M., Ferretti, Adrián, García, Ayelén G., Mauri, Aldana, Simonetto, Carla, Hijano, Diego R., Lawrence, Andrea, Acosta, Patricio L., Caballero, Mauricio T., Paredes Rojas, Yésica, Ibañez, Lorena I., Melendi, Guillermina A., Rey, Félix A., Damonte, Elsa B., Harris, Eva, Polack, Fernando P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2017; Elsevier
• Subjects: Animals; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; CD8+ T lymphocytes; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line; Cross Reactions - immunology; Dengue - immunology; Dengue - metabolism; Dengue - virology; Dengue virus; Dengue Virus - classification; Dengue Virus - immunology; Disease Models, Animal; Immune response; Immunocompetent mouse model; Immunoglobulin G - immunology; Lymphocyte Depletion; Mice; Mice, Knockout; Research Paper; Secondary infection; Serogroup; Severity of Illness Index; T-Cell Antigen Receptor Specificity - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Viral Load; Secondary infection; Immune response; Dengue virus; Immunocompetent mouse model; CD8+ T lymphocytes; CD8(+) T lymphocytes
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2017.04.033

Dengue is the most prevalent arthropod-borne viral disease worldwide and is caused by the four dengue virus serotypes (DENV-1-4). Sequential heterologous DENV infections can be associated with severe disease manifestations. Here, we present an immunocompetent mouse model of secondary DENV infection using non mouse-adapted DENV strains to investigate the pathogenesis of severe dengue disease. C57BL/6 mice infected sequentially with DENV-1 (strain Puerto Rico/94) and DENV-2 (strain Tonga/74) developed low platelet counts, internal hemorrhages, and increase of liver enzymes. Cross-reactive CD8+ T lymphocytes were found to be necessary and sufficient for signs of severe disease by adoptively transferring of DENV-1-immune CD8+T lymphocytes before DENV-2 challenge. Disease signs were associated with production of tumor necrosis factor (TNF)-α and elevated cytotoxicity displayed by heterotypic anti-DENV-1 CD8+ T lymphocytes. These findings highlight the critical role of heterotypic anti-DENV CD8+ T lymphocytes in manifestations of severe dengue disease. •Heterotypic anti-DENV-1 CD8+ T cells are critical for signs of severe dengue disease in sequentially DENV-2 infected mice•Production of TNF-α by heterotypic anti-DENV-1 CD8+ T lymphocytes is critical for signs of severe dengue disease•Anti-DENV-1 CD4+ T lymphocytes also contribute to severe dengue disease Talarico et al. present an immunocompetent mouse model of dengue virus secondary infection which shows signs of severe dengue disease upon heterotypic infection with DENV-1 (PR/94) followed by DENV-2 (Tonga/74). In this model cross-reactive CD4+ and CD8+ T cells contribute to disease, while anti-DENV heterotypic antibodies do not play a critical role in pathogenesis.