Inescapable Need for Neutrophils as Mediators of Cellular Innate Immunity to Acute Pseudomonas aeruginosa Pneumonia
Inescapable Need for Neutrophils as Mediators of Cellular Innate Immunity to Acute Pseudomonas aeruginosa Pneumonia
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DOI：
10.1128/iai.00501-09
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发表时间：
2009-12-01
影响因子：
3.1
通讯作者：
Pier, Gerald B.
中科院分区：
文献类型：
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作者：
Koh, Andrew Y.;Priebe, Gregory P.;Pier, Gerald B.
铜绿假单胞菌是肺炎的主要原因，并且已经提出先天免疫系统的许多组分在预防肺部感染中发挥重要作用。然而，尚未利用有力的实验系统来鉴定介导对肺部感染的先天免疫的压倒性的关键效应物。由于先天免疫的许多重要组成部分参与了多形核中性粒细胞（PMN）向感染组织的募集和激活，我们假设，这些细胞和因子正确募集到肺中所需的细胞和因子包括先天免疫的主要介质。在血小板减少小鼠中，鼻内（i.n.）低至10 - 100 CFU/小鼠的铜绿假单胞菌剂量产生了致命的肺部感染，而非血小板减少症小鼠的剂量为10（7）-> 10（8）CFU。当i.n.给药时，缺乏成熟淋巴细胞的小鼠的死亡率仅出现非常适度的增加，而肺泡巨噬细胞耗竭的小鼠的死亡率未增加。绿脓杆菌重组小鼠粒细胞集落刺激因子增加了i.n.绿脓杆菌接种。MyD 88（-/-）小鼠不能将PMN募集到肺部，对致命的铜绿假单胞菌肺部感染高度敏感，< 120 CFU的细菌剂量是致命的。在MyD 88（-/-）小鼠中，激活MyD 88非依赖性途径将PMN募集到肺部，导致增强对铜绿假单胞菌肺部感染的保护。总体而言，在没有中性粒细胞的情况下，小鼠不能抵抗极小细菌剂量的铜绿假单胞菌肺部感染。不可避免地需要局部PMN募集和活化来介导对铜绿假单胞菌肺部感染的先天免疫。
Pseudomonas aeruginosa is a leading cause of pneumonia, and many components of the innate immune system have been proposed to exert important effects in preventing lung infection. However, a vigorous experimental system to identify an overriding, key effector mediating innate immunity to lung infection has not been utilized. As many of the important components of innate immunity are involved in recruitment and activation of polymorphonuclear neutrophils (PMNs) to infected tissues, we hypothesized that the cells and factors needed for their proper recruitment to the lung comprised the major mediators of innate immunity. In neutropenic mice, intranasal (i.n.) doses of P. aeruginosa as low as 10 to 100 CFU/mouse produced a fatal lung infection, compared with 10(7) to > 10(8) CFU for nonneutropenic mice. There was only a very modest increased mortality in mice lacking mature lymphocytes and no increased mortality in mice depleted of alveolar macrophages when administered i.n. P. aeruginosa. Recombinant mouse granulocyte colony-stimulating factor increased survival of neutropenic mice after i.n. P. aeruginosa inoculation. MyD88(-/-) mice, which cannot recruit PMNs to the lungs, were highly susceptible to fatal P. aeruginosa lung infection, with bacterial doses of < 120 CFU being lethal. Activation of a MyD88-independent pathway for PMN recruitment to the lungs in MyD88(-/-) mice resulted in enhanced protection against P. aeruginosa lung infection. Overall, in the absence of PMNs, mice cannot resist P. aeruginosa lung infection from extremely small bacterial doses. There is an inescapable requirement for local PMN recruitment and activation to mediate innate immunity to P. aeruginosa lung infection.