Role of the chemokine receptors CCR1, CCR2 and CCR4 in the pathogenesis of experimental dengue infection in mice

• Published in: PloS one Vol. 5; no. 12; p. e15680
• Main Authors: Guabiraba, Rodrigo, Marques, Rafael Elias, Besnard, Anne-Gaëlle, Fagundes, Caio T, Souza, Danielle G, Ryffel, Bernhard, Teixeira, Mauro M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29-12-2010; Public Library of Science (PLoS)
• Subjects: Alanine Transaminase - metabolism; Analysis; Animal tissues; Animals; Aquatic insects; Aspartate Aminotransferases - metabolism; Biology; CC chemokine receptors; CCL17 protein; CCL3 protein; CCR1 protein; CCR2 protein; Cell activation; Chemokine receptors; Chemokines; Cytokines; Dengue; Dengue - metabolism; Dengue fever; Dengue virus; Dengue Virus - metabolism; Disease; Embryology; Health aspects; Immunology; Infection; Infections; Inflammation; Interferon-gamma - metabolism; Interleukin 6; Interleukin-6 - metabolism; Lethality; Leukocytes; Life Sciences; Ligands; Liver; Liver diseases; Lymphopenia; Male; Medicine; Mice; Mice, Inbred C57BL; Monocyte chemoattractant protein 1; Pathogenesis; Peroxidase - metabolism; Phenotypes; Public health; RANTES; Receptors; Receptors, CCR1 - metabolism; Receptors, CCR2 - metabolism; Receptors, CCR4 - metabolism; Sepsis; Spleen; Thrombocytopenia; Transaminases; Tumor necrosis factor-α; Vector-borne diseases; Viral diseases; Viral infections; Viruses; γ-Interferon; Brazil; France; Russia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0015680

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.