TNF-α单抗使用后易感染金黄色葡萄球菌的机制研究

Anti-TNF-α therapy has provided effective treatment for a number of debilitating illnesses such as rheumatoid arthritis and was found to be associated with an increased risk of systemic and local infection of Staphylococcus aureus. It indicates that TNF-α probably plays an important role on the host defense against S. aureus. However, the underlying mechanisms are still unknown. We will use the TNF-α antibody or TNF-α-/- and TNFR1-/- mice to interrupt the TNF-α/TNFR1 signaling pathway and establish the infection model by intraperitoneal or intratracheal instillation of S.aureus.The production of inflammatory cytokines (IL-6,IL-1β, IL-17, IL-22, IL-25),chemotactic factors (KC,MIP-2) and bone marrow differentiation factors (GM-CSF,G-CSF) in the lung, spleen and serum will be detected. The number of neutrophils and the bacterial load of S. aureus in these tissues are also counted. Furthermore, we want to investigate whether intratracheal administration of KC and MIP-2 can rebulit the host defense agianst S. aureus in TNF-α and TNFR1 deficient mice. Our study is aimed to illustrate the mechanisms of TNF-α antibody induced-susceptibility to S. aureus infection and try to find an applicable way for prevention and treatment of S. aureus infection.

临床使用抗肿瘤坏死因子-α(TNF-α)单抗治疗类风湿性关节炎，继发系统性和局部金黄色葡萄球菌感染的风险显著增加。这提示TNF-α在宿主抵抗金葡菌感染中起着重要作用，但是TNF-α缺乏如何影响机体天然免疫反应的具体机制并不明确。我们利用中和性TNF-α单抗或TNF-α和TNF受体1(TNFR1)基因敲除小鼠阻断体内TNF-α/TNFR1信号通路，通过腹腔注射或气道滴注的方法分别建立系统性和肺部金葡菌感染模型，观察小鼠感染早期肺脏、脾脏和血清中炎症因子(IL-6、IL-1β、IL-17、IL-22、IL-25),趋化因子(KC、MIP-2)和骨髓分化因子(GM-CSF、G-CSF)的变化，同时检测组织中性粒细胞数目、功能和金葡菌负荷的变化。最后，我们在TNF-α/TNFR1缺失小鼠的全身或气道局部回输KC和MIP-2，观察能否重建机体对金葡菌的抵抗力。研究将为金葡菌感染的防治提供可行的方法。

TNF-α信号通路在宿主抵抗金葡菌感染中起着重要作用，但TNF-α缺乏如何影响机体天然免疫反应的具体机制并不明确。我们的研究发现：（1）与对照组比较,TNF受体1(TNFR1) -/-小鼠的系统性金葡菌感染中，血液中性粒细胞数目较对照组降低，小鼠肺脏、脾脏和血清中细菌负荷增加。（2）与对照组比较, TNF-α -/-小鼠肺组织中性粒细胞浸润明显减少,中性粒细胞功能降低, 肺组织细菌负荷增加。（3）TNF-α-/-小鼠的气道回输KC和MIP-2，可以降低 肺部细菌负荷。（4）与对照组比较，Akt1-/-小鼠感染金葡菌后，生存率明显升高，肺部细菌负荷降低，说明Akt1分子负调控机体抗金葡菌天然免疫。上述研究将为金葡菌感染的防治提供新的思路。