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Maintenance of acquired resistance to Mycobacterium tuberculosis by L form mycobacteria macrophages

L型分枝杆菌巨噬细胞维持对结核分枝杆菌的获得性抗性

基本信息

批准号：
07807063
负责人：
KITA Eiji
金额：
$ 1.15万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07807063/
关键词：
tuberculosis intracellular parasite L forms cellular immunity BCG 抗酸菌感染症マクロファージ in situ PCR 免疫維持機構

项目摘要

The present study was done to prove our hypothesis that long-lived acquired resistance of humans to Mycobacterium tuberculosis is ascribed to the transformation of M.tuberculosis into L-form M.tuberculosis in macrophages localized at granulomatous lesions. To determine whether mycobacteria can transform into L forms in vivo, murine BCG infection model was used.Results obrtained herein were as follows :1) BCG transformed into L forms in Bcg^r mice after 60 days of infection, and treatment of infected Bcg^s miced with isoniazid (INH) induced the transformation of BCG into L forms.2) L-form BCG was detected in mononuclear cells of granulomatous lesions in the lung by the in-situ PCR.3) IFN-gamma was responsible for the transformation of intracellular BCG into L forms.4) Bcg^s mice immunized with L-form BCG or colonized with L-form BCG were immune from an intravenous infection with a lethal dose of BCG.5) Reversion of L-form BCG to parental BCG was achieved by treating L form-colonized mice with estrogen or TNF-alpha. This reversion was associated with the enhanced production of TNF-alpha and TGF-beta.6) In L form-colonized mice, mRNAs for IL-1, IL-12 and IFN-gamma were strongly expressed after an intravenous infection with a lethal dose of BCG.These data strongly suggest that transformation of BCG into L forms contribute to the maintenance of acquired resistance to infection with a lethal dose of BCG.Such a mechanism is possibly applied to human mycobacterial immunity which can last over a long period.

本研究旨在验证我们的假设，即人类对结核分枝杆菌的长期获得性耐药归因于结核分枝杆菌在肉芽肿性病变处的巨噬细胞内向L型结核分枝杆菌的转化。为了确定分枝杆菌能否在体内转化为L形式，采用小鼠卡介苗感染模型，结果如下：1)卡介苗在卡介苗感染60d后转化为L形式，2)原位聚合酶链式反应在肺肉芽肿病变的单核细胞中检测到L型卡介苗。3)干扰素-γ负责细胞内卡介苗向L型的转化。4)L型卡介苗免疫或L型卡介苗定植的卡介苗对致死剂量的卡介苗静脉感染获得免疫。5)用雌激素或肿瘤坏死因子-α处理L型定植的小鼠，获得L型卡介苗向亲代卡介苗的逆转。6)致死剂量的卡介苗静脉感染后，IL-1、IL-12和干扰素-γ的mRNAs有较强的表达。这些数据有力地表明，将卡介苗转化成L形式有助于维持对致死剂量的卡介苗感染的获得性抵抗力。这种机制可能适用于人类分枝杆菌免疫，这种机制可以持续很长时间。