Dysregulated interferon-gamma responses during lethal cytomegalovirus brain infection of IL-10-deficient mice
Dysregulated interferon-gamma responses during lethal cytomegalovirus brain infection of IL-10-deficient mice
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DOI：
10.1016/j.virusres.2007.05.022
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发表时间：
2007-12-01
期刊：
影响因子：
5
通讯作者：
Lokensgard, James R.
中科院分区：
文献类型：
--
作者：
Cheeran, Maxim C. -J.;Hu, Shuxian;Lokensgard, James R.
小鼠巨细胞病毒（MCMV）脑感染诱导趋化因子产生的短暂增加，这先于CD3（+）淋巴细胞的浸润。在这项研究中，我们假设抗炎细胞因子的缺乏将导致持续的促炎性神经免疫反应。将MCMV直接脑室内注射到IL-10敲除（KO）小鼠中产生了意想不到的结果：虽然野生型动物控制了MCMV，但IL-10 KO动物的感染是致命的。IL-4 KO动物的相同感染不产生致死性疾病。为了进一步表征IL-10的作用，评估了来自野生型和IL-10 KO动物的感染脑组织的细胞因子和趋化因子水平以及病毒基因表达。这些数据显示从IL-10 KO动物获得的脑匀浆中干扰素（IFN）-γ和IFN-γ诱导的趋化因子CXCL9和CXCL10以及IL-6的水平大大升高。但MCMV病毒载量、糖蛋白B mRNA水平。感染性病毒的滴度在IL-10 KO和野生型动物中相似。采用流式细胞术将从小鼠脑组织中分离的细胞分离成不同的细胞群，沿着随后的定量RT实时PCR显示，脑浸润的CD 45（hi）/CD 11b（-）和CD 45（hi）/CD 11b（int）是脑中IL-10的细胞来源。综上所述，这些数据表明，IL-10缺陷型小鼠的MCMV脑感染导致致死性疾病，其在存在失调的IFN-γ介导的神经免疫应答的情况下发生。(c)2007年爱思唯尔B.V.保留所有战斗。
Murine cytomegalovirus (MCMV) brain infection induces a transient increase in chemokine production, which precedes the infiltration of CD3(+) lymphocytes. In this study, we hypothesized that an absence of anti-inflammatory cytokines would result in sustained proinflammatory neuroimmune responses. Direct intracerebroventricular injection of MCMV into IL-10 knockout (KO) mice produced an unexpected result: while wild-type animals controlled MCMV, the infection was lethal in IL-10 KO animals. Identical infection of IL-4 KO animals did not produce lethal disease. To further characterize the role of IL-10, infected brain tissue from both wild-type and IL-10 KO animals was assessed for cytokine and chemokine levels, as well as viral gene expression. These data show vastly elevated levels of interferon (IFN)-gamma, and the IFN-gamma- inducible chemokines CXCL9 and CXCL10, as well as IL-6 in brain homogenates obtained from IL-10 KO animals. However, MCMV viral load, glycoprotein B mRNA levels. and titers of infectious virus were similar in both IL-10 KO and wild-type animals. Separation of cells isolated from murine brain tissue into distinct populations using FACS, along with subsequent quantitative RT real-time PCR, showed that brain-infiltrating CD45(hi)/CD11b(-) and CD45(hi)/CD11b(int) were the cellular source of IL-10 in the brain. Taken together, these data demonstrate that MCMV brain infection of IL-10-deficient mice causes lethal disease, which occurs in the presence of a dysregulated IFN-gamma-mediated neuroimmune response. (c) 2007 Elsevier B.V. All fights reserved.