2021 Fiscal Year Final Research Report
Identification of host genes that regulate neutralizing antibody production upon retrovirus infections and their mechanisms of action
| Project/Area Number |
19H03481
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 49060:Virology-related
|
|---|
| Research Institution | Kindai University |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
博多 義之 近畿大学, 医学部, 講師 (30344500)
塚本 徹雄 近畿大学, 医学部, 助教 (80750223)
|
|---|
| Project Period (FY) |
2019-04-01 – 2022-03-31
|
| Keywords | 中和抗体 / 宿主因子 / APOBEC3 / ゲノム編集 / ノックインマウス / 免疫組織化学 / Bリンパ球 / 胚中心 |
|---|
| Outline of Final Research Achievements |
In the process of identifying a host gene that regulates the production of neutralizing antibodies (Ab) upon retrovirus infection, we found genetic polymorphisms at the mouse Apobec3 locus. However, how this cytidine deaminase could affect Ab production was unclear. One hypothesis was that APOBEC3 (A3) might affect somatic hypermutation in B lymphocytes. To examine this, we established knock-in strains of mice that express A3 protein tagged with an in-frame FLAG peptide. Tagged A3 was detected in B cells, and distinctive high expression was observed in germinal center cells. Antigenic stimulation increased germinal center cells but A3 expression levels in each cell did not change. Further, in the presence of A3 processing of viral gag gene products was hampered and immature particles increased among budding virions. Thus, A3 may indirectly affect Ab production through protecting B cells from infection and increasing antigenically intact but non-replicating immature virions.
|
| Free Research Field |
ウイルス学
|
| Academic Significance and Societal Importance of the Research Achievements |
従来解析が困難であったAPOBEC3の生体内局在を、CRISPR-Cas9法によるタグノックインマウス作製で初めて明らかにした。APOBEC3がウイルス中和抗体産生を制御する機構として、Bリンパ球における体細胞突然変異誘発の関与が仮定されていたが、否定的となった。このノックインマウスは、今後炎症や発がん過程におけるAPOBEC3発現と局在の変化を解析するのに有用である。
ウイルス中和抗体産生制御機序の解明は感染防御ワクチン開発の基礎であり、今回Bリンパ球におけるウイルス感染制限と不全粒子による免疫刺激が示唆されたことから、サブユニットワクチンやmRNAワクチンの優位性が支持される。
|
