Prion protein protects mice from lethal infection with influenza A virus
| Project/Area Number |
16K10029
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Pediatrics
|
|---|
| Research Institution | The University of Tokushima |
|---|
Principal Investigator |
CHIDA Junji 徳島大学, 先端酵素学研究所(次世代), 助教 (20437651)
|
|---|
| Research Collaborator |
HARA Hideuki
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
|---|
| Keywords | インフルエンザ / プリオン蛋白質 / 抗プリオン抗体 / 脳症 / 多臓器不全 / インフルエンザAウイルス / 抗PrP抗体 / 換気障害 / 浮腫 / 活性酸素 / 抗酸化酵素 / 銅イオン / プリオン / インフルエンザウイルス / インフルエンザ脳症 / Src family kinase / ミトコンドリア |
|---|
| Outline of Final Research Achievements |
Compared with wild-type (WT) mice, PrP-KO mice (KO) were highly susceptible to influenza A viruses (IAVs), with higher mortality. Infected KO lungs were severely injured, with higher inflammation of epithelial cells, and contained higher reactive oxygen species (ROS) than WT lungs. Treatment with a ROS scavenger or an inhibitor of xanthine oxidase, a major ROS-generating enzyme in IAV-infected lungs, rescued KO mice from the lethal infection with IAV. Moreover, KO mice transgenic for PrP with a deletion of the Cu-binding OR region, Tg(ΔOR)/KO mice, were also highly susceptible to IAV infection. These results indicate that PrP has a protective role against lethal infection with IAVs through the Cu-binding OR region by reducing ROS in infected lungs. Cu content and the activity of SOD1, were lower in KO and Tg(ΔOR)/KO lungs than in WT lungs. It is thus conceivable that PrP functions to maintain Cu content and regulate SOD1 through the OR region in lungs.
|
| Academic Significance and Societal Importance of the Research Achievements |
これまでPrPは脳の神経細胞で特に高発現していること、PrPの構造変異体(異常型PrP)は凝集体を形成し、プリオン病を引き起こすことが知られている。しかし、PrPのKOマウスは正常に成長することから、PrPの生体機能は不明であった。従って、本研究はこれまで不明であったPrPの生体機能を解明する独創的研究であり、インフルエンザの病態の理解のみならずプリオン病の理解にも繋がる。本研究ではPrPが肺を構成する肺胞上皮やクララ細胞内の銅イオン濃度を保持することでSOD1の酵素活性を調節し、その結果、IAV感染により産生されるROSを不活化し、インフルエンザの重症化を軽減していることを明確にした。
|
Report
(4 results)
Research Products
(15 results)
