Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. Recent clinical data have shown an association between levels of different
chemokines in plasma and severity of
dengue. We evaluated the role of
CC chemokine receptors CCR1, CCR2 and CCR4 in an experimental model of DENV-2
infection in mice.
Infection of mice induced evident clinical disease and tissue damage, including
thrombocytopenia, hemoconcentration,
lymphopenia, increased levels of
transaminases and pro-inflammatory
cytokines, and lethality in WT mice. Importantly, infected WT mice presented increased levels of
chemokines CCL2/JE, CCL3/MIP-1α and CCL5/
RANTES in spleen and liver. CCR1⁻/⁻ mice had a mild phenotype with disease presentation and lethality similar to those of WT mice. In CCR2⁻/⁻ mice, lethality, liver damage, levels of
IL-6 and IFN-γ, and leukocyte activation were attenuated. However,
thrombocytopenia, hemoconcentration and systemic TNF-α levels were similar to infected WT mice.
Infection enhanced levels of CCL17/TARC, a CCR4
ligand. In CCR4⁻/⁻ mice, lethality, tissue injury and systemic
inflammation were markedly decreased. Despite differences in disease presentation in CCR-deficient mice, there was no significant difference in viral load. In conclusion, activation of
chemokine receptors has discrete roles in the pathogenesis of
dengue infection. These studies suggest that the
chemokine storm that follows severe primary
dengue infection associates mostly to development of disease rather than protection.