| Project/Area Number |
14570269
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Virology
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
YOKOTA Shin-ichi Sapporo Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (10325863)
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| Co-Investigator(Kenkyū-buntansha) |
FUJII Nobuhiro Sapporo Medical University, School of Medicine, Professor, 医学部, 教授 (90133719)
YOKOSAWA Noriko Sapporo Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (50167722)
TAMAKI Okabayashi Sapporo Medical University, School of Medicine, Instructor, 医学部, 助手 (10359995)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | Herpes simplex virus / interferon / cellular signal transduction / viral replication / SOCS3 / protein kinase inhibitor / Jak3 inhibitor / 生体防御 / ウイルス感染 / ヘルペスウイルス / 細胞内情報伝達 / JAK / STAT経路 / negative regulation / SCOS-3 / IRF / virion host shutoff / 蛋白質リン酸化 |
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| Research Abstract |
Previously, we found that HSV-1 suppressed interferon (IFN) signaling pathway in amnion cell line FLduring early phase of (a couple of hours after) infection. In this study, we examined the molecular mechanism of suppression of interferon (IFN) signal transduction during HSV-1 infection. Upregulation of a host JAK/ STAT pathway negative regulator, suppressor of cytokine signaling-3 (SOCS3), was observed during early stage (within 1 h) of HSV-1 infection. The induced SOCS3 contributed to suppression of IFN signaling.
Inducibility of SOCS3 was varied among cell lines. High responders, such as FLand T cell line CCRF-CEM, showed rapid viral replication and resulted in a lytic infection. On the other hand, non-responders, such as monocytic cell line U937 and THP-1, and Bcell line AKATA, showed no suppression of IFN signal transduction and resulted in a persistent or prolonged infection with continuous production of infectious virus with a low titer.
The induction of SOCS3 by HSV-1 should occur via STAT3 activation immediately after HSV-1 infection. Both STAT3 phosphorylation and SOCS3 induction were inhibited by Jak3 inhibitor, WHI-P131. Treatment with WHI-P131 or transfection of antisense oligonucleotides specific for SOCS3 dramatically suppressed replication of HSV-1 in FLcells. The suppression was partially released in the presence of neutralizing anti-IFN-α/β antibodies.
Lines of evidence indicate that induction of SOCS3 by HSV-1 infection is a important host cell factor determining cell-type specificity of efficient HSV-1 replication. Role of the induced SOCS3 is suggested to be suppression of the IFN signaling, which generates antiviral state of host cells. Furthermore, inhibition of SOCS3 can suppress HSV-1 replication, so it should be a novel target for therapeutic agent against viral infection.
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