| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Measles is a highly contagious viral diseases with fever and rash, particularly in pediatric. Suppression of the host immune response by measles virus (MeV) is a major cause of the high morbidity and mortality rates of acute measles, perhaps due to the role of immunosuppression in secondary infection. In the present study, we propose a novel immunosuppression mechanism of MeV in monocytic cells.
We found that the virus-induced and lipopolysaccharide (LPS)-induced activation of NF-κB and AP-1 was suppressed in monocytic cells infected with MeV, but not in infected epithelial cells. In the infected cells, LPS treatment failed to induce formation of active protein kinase complex containing TAK1, TAB2 and TRAF6, which dissociates from Toll-like receptor complexes containing IRAK1.Ubiquitin-modifying enzyme A20, which is an NF-κB-dependent gene and a host negative feedback regulator of NF-κB, was dramatically upregulated in infected monocytic cells, but not in infected epithelial cells. We demonstrated that MeV phosphoprotein (P protein) expression was necessary and sufficient for the induction ofA20. A negative regulatory motif (ELIE motif) in the A20 promoter was important for transcriptional upregulation of A20 by MeV. And the P protein interacted indirectly with the ELIE motif, and released the suppression of A20 transcription, independent to NF-κB.
Suppression of NF-κB and AP-1 activation, namely immunological silencing, in MeV-infected monocytic cells may be a strategy utilized by MeV to escape rejection and allow the spread of infection throughout the entire body via the blood stream. We consider that P-deficient MeV is a candidate for live-vaccine, which does not cause immunosuppression.
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