The C3a-receptor as modulator of the specific cellular immune-response in the mouse-model of Chlamydia psittaci lung infection

衣原体是感染粘膜的细胞内细菌。来自鸟类的人畜共患鹦鹉热衣原体（Cps）菌株可引起危及生命的肺炎，并在人类中全身传播。最近的研究表明，这种危险的病原体是德国大约2%的社区获得性肺炎的原因。此外，在接触受感染的禽鸟后，不时会有较小规模的爆发。补体系统被病原体的各种表面分子激活。然而，坏死的宿主细胞和免疫复合物也会触发这种级联反应。补体起促炎作用。然而，在其激活期间释放的介质C3 a和C5 a也可以增强特异性免疫应答。在小鼠感染Cps期间，补体在早期时间点被激活。补体因子C3以及C3 a及其受体（C3 aR）在防御这种细菌中起重要作用。在缺乏C3 aR的情况下，控制胞内病原体所需的T细胞亚群的数量减少。在此背景下，本项目将重点放在C3 a/C3 aR作为开发针对肺中Cps的有效特异性免疫应答的基石。我们希望更好地了解C3 a/C3 aR和补体系统在与呼吸道粘膜细胞、树突状细胞（DC）和各种T细胞亚群相互作用中的作用。我们希望确定所涉及的C3 a依赖性细胞，并描述C3 a在这种情况下的作用。我们想弄清楚细胞对C3 a的直接反应有多大，以及其他C3 aR表达细胞的间接作用（即释放的不同介质）有多大。在这种情况下，我们要阐明在细胞培养中Cps感染的肺上皮细胞合成和局部激活补体因子的程度，以及粘膜细胞如何通过细胞因子与DCs和T细胞相互作用，我们正在研究不同的问题，这些问题都旨在阐明补体和C3 a/C3 aR导致改善对细胞内细菌的保护的机制。我们将在该模型中详细获得的许多结果很可能也适用于其他细胞内肺病原体，或引起亚急性-慢性病程的细胞外病原体。从长远来看，我们的研究结果可能有助于通过免疫调节来改善肺部感染的治疗效果。

Chlamydia are intracellular bacteria infecting mucosa. Zoonotic Chlamydia psittaci (Cps) strains from birds cause life-threatening pneumonia with systemic spread in humans. Newer studies indicate that this dangerous pathogen is responsible for roughly 2% of community acquired pneumoniae in Germany. Moreover, from time to time there are smaller outbreaks after contact with infected birds.The complement system is activated by various surface molecules of pathogens. However, necrotic host-cells and immune-complexes also trigger this cascade. Complement acts proinflammatory. Yet, the mediators C3a and C5a which are released during its activation can also augment the specific immune-response. It is only partially understood how that happens.During mouse infection by Cps complement is activated at an early time point. Complement factor C3 as well as C3a with its receptor (C3aR) play important roles in the defense against this germ. In absence of C3aR the number of T cell subsets which are needed to control intracellular pathogens is reduced.On this background, this project focuses on C3a/C3aR as a corner stone in the development of an effective specific immune-response against Cps in the lung. We want to gain a better understanding of the role of C3a/C3aR and the complement system in the interaction with respiratory mucosa cells, dendritic cells (DC) and various T cell subpopulations. We want to identify the involved C3a-dependent cells and characterize how C3a acts in this setting. We want to clarify how far cells respond directly to C3a and how far indirect effects (i.e. different mediators released) from other C3aR-expressing cells are involved. In this context we want to elucidate in cell culture how far Cps infected lung epithelial cells synthesize and locally activate complement factors, and how mucosal cells interact via cytokines with DCs and T cells.We are following different questions which all aim on the elucidation of the mechanisms by which complement and C3a/C3aR lead to improved protection against an intracellular bacterium. Many results which we will obtain in detail in this model can most likely also be applied for other intracellular lung pathogens, or for extracellular pathogens which cause a subacute-chronic course of disease. On the long run our results might help to improve therapeutically by immune-modulation the outcome of lung infections.