Morrison Brad E, Park Stacy J, Mooney Jill M, Mehrad Borna
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9034, USA.
J Clin Invest. 2003 Dec;112(12):1862-70. doi: 10.1172/JCI18125.
Invasive aspergillosis is a severe pneumonia that is usually fatal despite currently available therapy. The disease disproportionately afflicts immunocompromised patients, indicating the critical importance of the immune status of the host in this infection, but the defense mechanisms against this pathogen remain incompletely understood. In the current study, we hypothesized that the chemokine ligand monocyte chemotactic protein-1, also designated CC chemokine ligand-2 (MCP-1/CCL2) is necessary for effective host defense against invasive aspergillosis in immunocompromised hosts. We found a rapid and marked induction of MCP-1/CCL2 in the lungs of neutropenic mice with invasive aspergillosis. Neutralizing MCP-1/CCL2 resulted in twofold greater mortality and greater than threefold increase in pathogen burden in the lungs. Neutralization of MCP-1/CCL2 also resulted in reduced recruitment of NK cells to the lungs at early time points, but did not affect the number of other leukocyte effector cells in the lungs. Ab-mediated depletion of NK cells similarly resulted in impaired defenses against the infection, resulting in a greater than twofold increase in mortality and impaired clearance of the pathogen from the lungs. These data establish MCP-1/CCL2-mediated recruitment of NK cells to the lungs as a critical early host defense mechanism in invasive aspergillosis and demonstrate NK cells to be an important and previously unrecognized effector cell in this infection.
侵袭性曲霉病是一种严重的肺炎，尽管有目前可用的治疗方法，通常仍会致命。该疾病在免疫功能低下的患者中更为常见，这表明宿主的免疫状态在这种感染中至关重要，但针对这种病原体的防御机制仍未完全了解。在本研究中，我们假设趋化因子配体单核细胞趋化蛋白-1（也称为CC趋化因子配体-2，即MCP-1/CCL2）对于免疫功能低下宿主有效抵御侵袭性曲霉病是必需的。我们发现在患有侵袭性曲霉病的中性粒细胞减少小鼠的肺部，MCP-1/CCL2迅速且显著诱导。中和MCP-1/CCL2导致死亡率增加两倍，肺部病原体负担增加超过三倍。中和MCP-1/CCL2还导致早期NK细胞向肺部的募集减少，但不影响肺部其他白细胞效应细胞的数量。抗体介导的NK细胞耗竭同样导致对感染的防御受损，死亡率增加超过两倍，且肺部病原体清除受损。这些数据表明，MCP-1/CCL2介导的NK细胞向肺部募集是侵袭性曲霉病中关键的早期宿主防御机制，并证明NK细胞是这种感染中一种重要且此前未被认识的效应细胞。
