Cheeran Maxim C-J, Hu Shuxian, Palmquist Joseph M, Bakken Thomas, Gekker Genya, Lokensgard James R
Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, MN, United States.
Virus Res. 2007 Dec;130(1-2):96-102. doi: 10.1016/j.virusres.2007.05.022. Epub 2007 Jul 12.
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.
鼠巨细胞病毒（MCMV）脑感染会诱导趋化因子产生短暂增加，这发生在CD3(+)淋巴细胞浸润之前。在本研究中，我们假设缺乏抗炎细胞因子会导致持续的促炎神经免疫反应。将MCMV直接脑室内注射到白细胞介素-10基因敲除（KO）小鼠体内产生了意想不到的结果：野生型动物能够控制MCMV，而感染在白细胞介素-10基因敲除动物中是致命的。对白细胞介素-4基因敲除动物进行相同的感染并未导致致命疾病。为了进一步明确白细胞介素-10的作用，我们评估了野生型和白细胞介素-10基因敲除动物感染后的脑组织中细胞因子、趋化因子水平以及病毒基因表达。这些数据显示，从白细胞介素-10基因敲除动物获得的脑匀浆中，干扰素（IFN）-γ、IFN-γ诱导的趋化因子CXCL9和CXCL10以及白细胞介素-6水平大幅升高。然而，白细胞介素-10基因敲除动物和野生型动物的MCMV病毒载量、糖蛋白B mRNA水平以及感染性病毒滴度相似。使用荧光激活细胞分选术（FACS）将从小鼠脑组织分离的细胞分成不同群体，随后进行定量逆转录实时聚合酶链反应（RT real-time PCR），结果表明脑浸润的CD45(hi)/CD11b(-)和CD45(hi)/CD11b(int)细胞是脑中白细胞介素-10的细胞来源。综上所述，这些数据表明，白细胞介素-10缺陷小鼠的MCMV脑感染会导致致命疾病，这种疾病发生在IFN-γ介导的神经免疫反应失调的情况下。
