Tse Hubert M, Josephy Steven I, Chan Edward D, Fouts Darren, Cooper Andrea M
Mycobacteria Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, CO 80523, USA.
J Immunol. 2002 Jan 15;168(2):825-33. doi: 10.4049/jimmunol.168.2.825.
Of the two common morphotypes of Mycobacterium avium, designated smooth transparent (SmT) or smooth opaque (SmO), the SmO morphotype is avirulent, whereas the SmT morphotype is virulent. The role of the host macrophage in determining these different virulence phenotypes was analyzed using an in vitro model of macrophage infection. Initial studies confirmed previous reports of the increased ability of the SmT bacteria to grow in macrophages; this increased virulence correlated with reduced induction of inflammatory cytokines. Examination of the response of the mitogen-activated protein kinase (MAPK) pathway following infection with either morphotype revealed that all three members of the MAPK pathway were activated. Pharmacologic inhibition of either the extracellular signal-regulated kinase (ERK) or p38(MAPK) pathways resulted in distinct consequences for the growth of the two morphotypes. In particular, inhibition of the p38(MAPK) resulted in attenuated growth of the SmT morphotype, which correlated with reduced PGE(2) production. Inhibition of cyclooxygenase 2 by indomethacin also inhibited growth of SmT, substantiating the role for PGE(2) in promoting the growth of SmT. In contrast, SmO induction of the ERK pathway was increased compared with the SmT morphotype, and inhibition of ERK resulted in decreased TNF-alpha synthesis and enhanced SmO growth. Pharmacologic inhibitors of the MAPK pathway were present for only the first 4 h of infection and yet had consequences for bacterial growth at 7 days. Therefore, the data suggest that induction of the MAPK pathway during uptake of bacteria is instrumental in determining the eventual fate of the bacteria.
在鸟分枝杆菌的两种常见形态型中，分别命名为光滑透明型（SmT）或光滑不透明型（SmO），SmO形态型无毒力，而SmT形态型有毒力。使用巨噬细胞感染的体外模型分析了宿主巨噬细胞在决定这些不同毒力表型中的作用。初步研究证实了先前关于SmT细菌在巨噬细胞中生长能力增强的报道；这种增加的毒力与炎症细胞因子诱导的减少相关。对感染任一形态型后丝裂原活化蛋白激酶（MAPK）途径的反应进行检查发现，MAPK途径的所有三个成员均被激活。对细胞外信号调节激酶（ERK）或p38（MAPK）途径进行药理抑制对两种形态型的生长产生了不同的影响。特别是，抑制p38（MAPK）导致SmT形态型的生长减弱，这与PGE（2）产生减少相关。吲哚美辛对环氧合酶2的抑制也抑制了SmT的生长，证实了PGE（2）在促进SmT生长中的作用。相比之下，与SmT形态型相比，SmO对ERK途径的诱导增加，抑制ERK导致TNF-α合成减少并增强SmO生长。MAPK途径的药理抑制剂仅在感染的前4小时存在，但对7天时的细菌生长有影响。因此，数据表明细菌摄取过程中MAPK途径的诱导有助于决定细菌的最终命运。
