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

Talarico, Laura B; Batalle, Juan P; Byrne, Alana B; Brahamian, Jorge M; Ferretti, Adrián; García, Ayelén G; Mauri, Aldana; Simonetto, Carla et al. · EBioMedicine · 2017

basic_science · Level V

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Abstract

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<sup>+</sup> T lymphocytes were found to be necessary and sufficient for signs of severe disease by adoptively transferring of DENV-1-immune CD8<sup>+</sup>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<sup>+</sup> T lymphocytes. These findings highlight the critical role of heterotypic anti-DENV CD8<sup>+</sup> T lymphocytes in manifestations of severe dengue disease.

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