The role of heterotypic DENV-specific CD8+T lymphocytes in the pathogenesis of Dengue Hemorrhagic fever

TALARICO, LB; HIJANO DR; BATALLE, JP; LAWRENCE A; DIAZ, LM; ACOSTA, PL; BRUM-ORNELAS C; MELENDI, GA; POLACK FP

Nashville

Simposio; Pediatrics Infectious Desases Retreat 2011; 2011

Vanderbilt University

Dengue virus (DENV) is the most common arboviral cause of illness worldwide. There is currently no licensed vaccine for prophylaxis or antivirals to treat the infection. The main hypotheses on the mechanism of illness for dengue hemorrhagic fever (DHF) involve heterotypic antibody enhancement and memory T lymphocytes cross-reactivity. We recently established a novel mouse model of DHF. Mice infected sequentially with DENV-1 and DENV-2 develop thrombocytopenia, capillary leakage, internal hemorrhages, and transaminitis. The aim of the preset work was to study the role of DENV-specific CD8+ T lymphocytes in DHF pathogenesis. In CD8+T and CD4+/CD8+T lymphocytes depleted C57BL/6 mice sequentially infected with DENV-1/DENV-2 we found significantly low levels of transaminases, CK, LDH, and higher platelet count, while CD4+T lymphocytes depleted mice showed moderately low levels of the same enzymes. Moreover, we found increased levels of CK and LDH and low platelet count in mice that received CD8+T cells from DENV-1 infected mice and later infected with DENV-2. The dominant H-2b restricted CD8+T lymphocyte responses as a result of sequential DENV-1/DENV- 2 infection were dominated by CTLs directed against epitopes of NS4b protein. These results show that CD8+T lymphocytes play a critical role in DHF pathogenesis, while CD4+T lymphocytes are less critical for the development of severe disease.