The Role of Heterotypic DENV-specific CD8+T Lymphocytes in an Immunocompetent Mouse Model of Secondary Dengue Virus Infection
Laura B. Talarico,
Juan P. Batalle,
Alana B. Byrne,
Jorge M. Brahamian,
Adrián Ferretti,
Ayelén G. García,
Aldana Mauri,
Carla Simonetto,
Diego R. Hijano,
Andrea Lawrence,
Patricio L. Acosta,
Mauricio T. Caballero,
Yésica Paredes Rojas,
Lorena I. Ibañez,
Guillermina A. Melendi,
Félix A. Rey,
Elsa B. Damonte,
Eva Harris,
Fernando P. Polack
Affiliations
Laura B. Talarico
Fundación INFANT, Buenos Aires, Argentina
Juan P. Batalle
Fundación INFANT, Buenos Aires, Argentina
Alana B. Byrne
Fundación INFANT, Buenos Aires, Argentina
Jorge M. Brahamian
Fundación INFANT, Buenos Aires, Argentina
Adrián Ferretti
Fundación INFANT, Buenos Aires, Argentina
Ayelén G. García
Fundación INFANT, Buenos Aires, Argentina
Aldana Mauri
Fundación INFANT, Buenos Aires, Argentina
Carla Simonetto
Fundación INFANT, Buenos Aires, Argentina
Diego R. Hijano
Fundación INFANT, Buenos Aires, Argentina
Andrea Lawrence
Department of Pediatrics, Vaccine Center, Vanderbilt University, Nashville, TN, USA
Patricio L. Acosta
Fundación INFANT, Buenos Aires, Argentina
Mauricio T. Caballero
Fundación INFANT, Buenos Aires, Argentina
Yésica Paredes Rojas
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Lorena I. Ibañez
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Guillermina A. Melendi
Fundación INFANT, Buenos Aires, Argentina
Félix A. Rey
Département de Virologie, Institut Pasteur, Unité de Virologie Structurale, Paris, France
Elsa B. Damonte
Laboratorio de Virología, Departamento de Química Biológica-IQUIBICEN (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Eva Harris
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
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.
