MyD88 Signaling Is Required for Efficient Innate and Adaptive Immune Responses to Paracoccidioides brasiliensis Infection
MyD88 Signaling Is Required for Efficient Innate and Adaptive Immune Responses to Paracoccidioides brasiliensis Infection
复制标题
DOI：
10.1128/iai.00375-10
复制
发表时间：
2011-06-01
影响因子：
3.1
通讯作者：
Calich, Vera L. G.
中科院分区：
文献类型：
--
作者：
Loures, Flavio V.;Pina, Adriana;Calich, Vera L. G.
巴西副球孢子菌（Paracoccidioides brasiliensis）是一种主要的二型真菌病原体，其与先天免疫细胞之间的初始相互作用机制尚待阐明。我们以前的研究表明，Toll样受体2（TLR 2）和TLR 4调节真菌细胞与巨噬细胞的初始相互作用以及进一步发展的适应性免疫模式。本研究的目的是评估MyD 88的作用，MyD 88是TLR用于激活肺副球孢子菌病炎症反应基因的衔接分子。用正常和MyD 88（-/-）C57 BL/6小鼠进行研究，所述小鼠用巴西巴斯德菌酵母细胞进行肠道感染。MyD 88（-/-）巨噬细胞显示与真菌酵母细胞的相互作用受损，并产生低水平的IL-12、MCP-1和一氧化氮，从而使真菌生长增加。与野生型（WT）小鼠相比，MyD 88（-/-）小鼠发生了更严重的肺部感染，并有明显的真菌细胞扩散到肝脏和脾脏。MyD 88（-/-）小鼠呈现低水平的Th 1、Th 2和Th 17细胞因子，抑制淋巴细胞增殖，并损害炎性细胞向肺的流入，并且该组细胞包括较低数量的中性粒细胞、活化的巨噬细胞和T细胞。非组织化的、融合的肉芽肿，其中含有大量的真菌细胞，是MyD 88（-/-）小鼠严重病变的特征;病变取代了几个器官的广泛区域。因此，MyD 88（-/-）小鼠无法控制真菌生长，并显示出显著降低的存活时间。总之，我们的研究结果表明，MyD 88信号转导在激活杀真菌机制和诱导针对巴西青霉的保护性先天和适应性免疫应答中是重要的。
The mechanisms that govern the initial interaction between Paracoccidioides brasiliensis, a primary dimorphic fungal pathogen, and cells of the innate immunity need to be clarified. Our previous studies showed that Toll-like receptor 2 (TLR2) and TLR4 regulate the initial interaction of fungal cells with macrophages and the pattern of adaptive immunity that further develops. The aim of the present investigation was to assess the role of MyD88, an adaptor molecule used by TLRs to activate genes of the inflammatory response in pulmonary paracoccidioidomycosis. Studies were performed with normal and MyD88(-/-) C57BL/6 mice intratracheally infected with P. brasiliensis yeast cells. MyD88(-/-) macrophages displayed impaired interaction with fungal yeast cells and produced low levels of IL-12, MCP-1, and nitric oxide, thus allowing increased fungal growth. Compared with wild-type (WT) mice, MyD88(-/-) mice developed a more severe infection of the lungs and had marked dissemination of fungal cells to the liver and spleen. MyD88(-/-) mice presented low levels of Th1, Th2, and Th17 cytokines, suppressed lymphoproliferation, and impaired influx of inflammatory cells to the lungs, and this group of cells comprised lower numbers of neutrophils, activated macrophages, and T cells. Nonorganized, coalescent granulomas, which contained high numbers of fungal cells, characterized the severe lesions of MyD88(-/-) mice; the lesions replaced extensive areas of several organs. Therefore, MyD88(-/-) mice were unable to control fungal growth and showed a significantly decreased survival time. In conclusion, our findings demonstrate that MyD88 signaling is important in the activation of fungicidal mechanisms and the induction of protective innate and adaptive immune responses against P. brasiliensis.