Immunopharmacology, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
PLoS One. 2010 Dec 29;5(12):e15680. 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.
登革热病毒（DENV）是一种通过蚊子传播的黄病毒，是许多热带国家的公共卫生问题。最近的临床数据表明，血浆中不同趋化因子的水平与登革热的严重程度之间存在关联。我们评估了 CC 趋化因子受体 CCR1、CCR2 和 CCR4 在登革热病毒 2 型（DENV-2）感染实验模型中小鼠中的作用。感染小鼠诱导了明显的临床疾病和组织损伤，包括血小板减少、血液浓缩、淋巴细胞减少、转氨酶和促炎细胞因子水平升高，以及野生型（WT）小鼠的致死性。重要的是，感染 WT 小鼠的脾脏和肝脏中趋化因子 CCL2/JE、CCL3/MIP-1α 和 CCL5/RANTES 的水平增加。CCR1⁻/⁻小鼠的表型较轻，疾病表现和致死率与 WT 小鼠相似。在 CCR2⁻/⁻小鼠中，致死率、肝损伤、IL-6 和 IFN-γ 水平以及白细胞激活减弱。然而，血小板减少、血液浓缩和全身 TNF-α 水平与感染的 WT 小鼠相似。感染增强了 CCL17/TARC 的水平，这是 CCR4 的配体。在 CCR4⁻/⁻小鼠中，致死率、组织损伤和全身炎症明显减少。尽管 CCR 缺陷小鼠的疾病表现存在差异，但病毒载量没有显著差异。总之，趋化因子受体的激活在登革热感染的发病机制中具有不同的作用。这些研究表明，严重原发性登革热感染后发生的趋化因子风暴主要与疾病的发展有关，而不是保护作用。
