CD180 and the Macrophage Response to Legionella pneumophila

描述（由申请方提供）：CD 180和嗜肺军团菌的巨噬细胞反应嗜肺军团菌（Lp）是一种革兰氏阴性细胞内细菌，感染人肺泡巨噬细胞并引起称为军团菌病（LD）的肺炎。CD 180（RP 105）是TLR家族的非信号传导成员，调节TLR 2和TLR 4功能，其在军团菌发病机制中的作用尚不清楚。我们假设CD 180调节小鼠和人类对Lp感染的易感性。我们用Lp感染骨髓来源的巨噬细胞，并在野生型和鞭毛蛋白缺陷型Lp菌株的一系列MOI中观察到与C57 BL/6对照相比，CD 180-/-小鼠中的复制显著增加。CD 180-/-巨噬细胞中Lp复制的增强与关键先天免疫细胞因子如IL-1、IL-6或TNF的释放无关。使用病例对照研究的个人从1999年爆发的军团病在荷兰，我们发现CD 180单核苷酸多态性与保护LD显着相关（OD 0.27-0.50）。这些多态性之一与单核细胞中CD 180表达降低相关。在这个应用中，我们建议在体外研究机制的CD 180依赖性宿主抵抗Lp感染的小鼠。此外，我们还将研究人类CD 180的变异体及其在调节单核细胞和巨噬细胞对Lp感染的反应中的作用。我们将研究是否改变CD 180的功能，通过多态性在人类或靶向基因缺失在小鼠中，改变宿主反应的鞭毛，细胞内细菌在分子和细胞水平。CD 180缺陷的个体提供了一个独特的机会来研究人CD 180变异的体外和体内效应，并且沿着CD 180-/-小鼠，将使我们能够研究CD 180在对Lp的先天免疫应答中的作用。从这些研究中获得的免疫遗传学模型将阐明宿主对Lp和可能的其他细胞内细菌引起的疾病的易感性机制，并最终为未来的治疗提供新的见解。

DESCRIPTION (provided by applicant): CD180 and the Macrophage Response to Legionella neumophila Legionella pneumophila (Lp) is a gram-negative intracellular bacterium that infects human alveolar macrophages and causes a pneumonic illness known as Legionnaire's Disease (LD). The role of CD180 (RP105), a non-signaling member of the TLR family that regulates TLR2 and TLR4 function, in Legionella pathogenesis is unknown. We hypothesized that CD180 regulates susceptibility to Lp infection in mice and humans. We infected bone-marrow derived macrophages with Lp and observed significantly greater replication in CD180-/- mice compared to C57BL/6 controls over a range of MOIs in both wildtype and flagellin-deficient Lp strains. The enhanced replication of Lp in CD180-/- macrophages was not associated with release of key innate immune cytokines, such as IL-1¿, IL-6, or TNF. Using a case-control study of individuals from a 1999 outbreak of Legionnaire's Disease in the Netherlands, we found CD180 single nucleotide polymorphisms that were significantly associated with protection from LD (OD 0.27-0.50). One of these polymorphisms was associated with decreased expression of CD180 in monocytes. In this application, we propose to examine the in vitro mechanisms underlying CD180-dependent host resistance to Lp infection in mice. In addition, we will examine human variants of CD180 and their role in regulating monocyte and macrophage responses to Lp infection. We will examine whether alteration of CD180 function, via polymorphisms in humans or targeted gene deletion in mice, changes the host response to a flagellated, intracellular bacteria at the molecular and cellular level. Individuals with CD180 deficiency provide a unique opportunity to study the in vitro and in vivo effects of human CD180 variation and, along with CD180-/- mice, will enable us to examine the role of CD180 in the innate immune response to Lp. The immunogenetic models derived from these studies will illuminate mechanisms of host susceptibility to diseases caused by Lp and possibly other intracellular bacteria and culminate in novel insights for future therapies.