Fremond Cécile M C, Nicolle Delphine M M, Torres David S, Quesniaux Valérie F J
Experimental and Molecular Genetics (GEM, FRE2358), Transgenose Institute, CNRS, 3Bb, rue de la Férollerie, 45071 Orléans cedex 2, France.
Microbes Infect. 2003 Oct;5(12):1070-81. doi: 10.1016/j.micinf.2003.06.001.
Live mycobacteria have been reported to signal through several pattern recognition receptors (PRR), among them toll-like receptor 4 (TLR4) and TLR2 in vitro. Here, we investigated the role of TLR4 in host resistance to Mycobacterium bovis (BCG) infection in vivo. In vitro, macrophages of TLR4 mutant C3H/HeJ mice infected with BCG expressed lower levels of TNF than controls, and TNF release was further decreased, although not completely absent, in the absence of TLR2. In vivo, TLR4 mutant C3H/HeJ and control C3H/HeOUJ mice were infected with BCG (2 x 10(6) CFU i.v.). Both TLR4 mutant and wild-type mice were able to control the infection and survived 8 months post-BCG infection. Macrophage activation with abundant acid-fast bacilli and expression of inducible nitric oxide synthase (iNOS) and MHC class II antigens was seen in both groups of mice. However, TLR4 mutant mice experienced an arrest of body weight gain and showed signs of increased inflammation, with persistent splenomegaly, increase in granuloma number and augmented neutrophil infiltration. Infection of TLR4-deficient mice with higher doses of BCG (1 and 3 x 10(7) CFU, i.v.) increased the inflammation in spleen and liver, associated with a transient, higher bacterial load in the liver. In summary, TLR4 mutant mice show normal macrophage recruitment and activation, granuloma formation and control of the BCG infection, but this is associated with persistent inflammation. Therefore, TLR4 signaling is not essential for early control of BCG infection, but it may have a critical function in fine tuning of inflammation during chronic mycobacterial infection.
据报道，活的分枝杆菌可通过几种模式识别受体（PRR）发出信号，其中包括体外的Toll样受体4（TLR4）和TLR2。在此，我们研究了TLR4在体内宿主对牛分枝杆菌（卡介苗）感染的抗性中的作用。在体外，感染卡介苗的TLR4突变型C3H/HeJ小鼠的巨噬细胞表达的肿瘤坏死因子（TNF）水平低于对照组，并且在没有TLR2的情况下，TNF释放进一步减少，尽管并未完全消失。在体内，TLR4突变型C3H/HeJ小鼠和对照C3H/HeOUJ小鼠经静脉注射感染了卡介苗（2×10⁶CFU）。TLR4突变型小鼠和野生型小鼠均能够控制感染，并在卡介苗感染后存活8个月。两组小鼠均可见巨噬细胞被大量抗酸杆菌激活以及诱导型一氧化氮合酶（iNOS）和MHC II类抗原的表达。然而，TLR4突变型小鼠体重增加停滞，并表现出炎症增加的迹象，伴有持续性脾肿大、肉芽肿数量增加和中性粒细胞浸润增加。用更高剂量的卡介苗（1和3×10⁷CFU，静脉注射）感染TLR4缺陷型小鼠会增加脾脏和肝脏的炎症，同时肝脏中细菌载量会短暂升高。总之，TLR4突变型小鼠表现出正常的巨噬细胞募集和激活、肉芽肿形成以及对卡介苗感染的控制，但这与持续性炎症有关。因此，TLR4信号传导对于卡介苗感染的早期控制并非必不可少，但它可能在慢性分枝杆菌感染期间炎症的微调中具有关键作用。
