Giles Steven S, Zaas Aimee K, Reidy Mike F, Perfect John R, Wright Jo Rae
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
PLoS One. 2007 Dec 26;2(12):e1370. doi: 10.1371/journal.pone.0001370.
Initiation of a protective immune response to infection by the pathogenic fungus Cryptococcus neoformans is mediated in part by host factors that promote interactions between immune cells and C. neoformans yeast. Surfactant protein A (SP-A) contributes positively to pulmonary host defenses against a variety of bacteria, viruses, and fungi in part by promoting the recognition and phagocytosis of these pathogens by alveolar macrophages. In the present study we investigated the role of SP-A as a mediator of host defense against the pulmonary pathogen, C. neoformans. Previous studies have shown that SP-A binds to acapsular and minimally encapsulated strains of C. neoformans. Using in vitro binding assays we confirmed that SP-A does not directly bind to a fully encapsulated strain of C. neoformans (H99). However, we observed that when C. neoformans was incubated in bronchoalveolar fluid, SP-A binding was detected, suggesting that another alveolar host factor may enable SP-A binding. Indeed, we discovered that SP-A binds encapsulated C. neoformans via a previously unknown IgG dependent mechanism. The consequence of this interaction was the inhibition of IgG-mediated phagocytosis of C. neoformans by alveolar macrophages. Therefore, to assess the contribution of SP-A to the pulmonary host defenses we compared in vivo infections using SP-A null mice (SP-A-/-) and wild-type mice in an intranasal infection model. We found that the immune response assessed by cellular counts, TNFalpha cytokine production, and fungal burden in lungs and bronchoalveolar lavage fluids during early stages of infection were equivalent. Furthermore, the survival outcome of C. neoformans infection was equivalent in SP-A-/- and wild-type mice. Our results suggest that unlike a variety of bacteria, viruses, and other fungi, progression of disease with an inhalational challenge of C. neoformans does not appear to be negatively or positively affected by SP-A mediated mechanisms of pulmonary host defense.
宿主对致病性真菌新型隐球菌感染产生保护性免疫反应的启动部分是由促进免疫细胞与新型隐球菌酵母相互作用的宿主因子介导的。表面活性蛋白A（SP-A）通过促进肺泡巨噬细胞对这些病原体的识别和吞噬作用，对肺部抵御多种细菌、病毒和真菌的宿主防御起到积极作用。在本研究中，我们调查了SP-A作为宿主抵御肺部病原体新型隐球菌的防御介质的作用。先前的研究表明，SP-A可与新型隐球菌的无荚膜和低荚膜菌株结合。通过体外结合试验，我们证实SP-A不会直接与新型隐球菌的完全荚膜菌株（H99）结合。然而，我们观察到，当新型隐球菌在支气管肺泡液中孵育时，可检测到SP-A的结合，这表明另一种肺泡宿主因子可能使SP-A能够结合。事实上，我们发现SP-A通过一种先前未知的IgG依赖性机制与荚膜化的新型隐球菌结合。这种相互作用的结果是抑制了肺泡巨噬细胞对新型隐球菌的IgG介导的吞噬作用。因此，为了评估SP-A对肺部宿主防御的贡献，我们在鼻内感染模型中比较了使用SP-A基因敲除小鼠（SP-A-/-）和野生型小鼠进行的体内感染情况。我们发现，在感染早期，通过细胞计数、TNFα细胞因子产生以及肺和支气管肺泡灌洗液中的真菌负荷评估的免疫反应是相同的。此外，新型隐球菌感染在SP-A-/-小鼠和野生型小鼠中的存活结果也是相同的。我们的结果表明，与多种细菌、病毒和其他真菌不同，吸入新型隐球菌引发的疾病进展似乎不受SP-A介导的肺部宿主防御机制的负面影响或正面影响。
