| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
The role of innate immune responses caused by NK cells and NO derived from brain macrophages during MCMV infection in the developing brains of C57BL/6 mice was investigated. The viral titer of the brains of neonatal mice inoculated with MCMV (half of LD50) peaked at 7 days post-infection (dpi) then declined. Viral replication in the brain of newborn mice was significantly enhanced by administration of anti-asialo-GM1 antibody, a specific inhibitor of NK cells, or L- N6-(1-imminoethyl)-lysine, a specific inhibitor of NO2. Thus, NK cells and NO contribute to viral clearance from the brain. At early phases of infection (3 dpi), the MCMV E1 antigen-positive cells and viral DNA were detected in cells of the lateral ventricle (V). At 7 dpi the E1-positive cells were found not only in cells of the lateral ventricle but also in the neurons of the hippocampus (Hp) and cortex (Cx). At a prolonged phase of infection (11 dpi), the E1-positive cells disap- peared from the ventricular wall, but pers
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isted in neurons (Figure 6A). At 7 dpi, in the ventricular wall, a GM1 (NK cell marker), NOS (macrophage marker) were expressed markedly, whereas in the hippocampus, although the E1 antigen was expressed in neurons, the markers of NK cells and macrophages were hardly expressed. Viral DNA was also hardly detected in neurons of the hippocampus.
It is hypothesised that some signals from the infected cells in the ventricular walls activate NK cells and macrophages. INF from NK cells may induce NOS in macrophages, then cytokines such as IL12 from the activated macrophages activate NK cells, resulting in lysis of the infected cells. In contrast, the prolonged infected neurons in the hippocampus may evade the innate immunity and transfer to persistent infection. It has been reported that innate immune responses begin with the recognition of MCMV-infected cells by NK cells via the interaction between the Ly49H molecule of NK cells and the m157 protein of MCMV on virus-infected cells. It is possible that expression of m157 proteins as ligands for Ly49 receptor of NK cells may be insufficient in MCMV-infected neurons to induce the innate immune response. Less
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