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。来自禽类的人兽共患鹦鹉热衣原体(CPS)菌株可导致危及生命的肺炎，并在人类中系统性传播。较新的研究表明，在德国，这种危险的病原体导致了大约2%的社区获得性肺炎。此外，与受感染的禽鸟接触后，不时会有较小的疫情爆发，补体系统会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体也会触发这种级联反应。补体起促炎作用。然而，在其激活过程中释放的介质C3a和C5a也可以增强特异性免疫反应。这是如何发生的还只有部分了解。在小鼠感染CPS的过程中，补体在早期被激活。补体C3和C3a及其受体(C3aR)在抵御这种细菌的过程中起着重要的作用。在缺乏C3aR的情况下，控制细胞内病原体所需的T细胞亚群的数量减少。在这种背景下，本项目将C3a/C3aR作为开发针对CPS的有效特异性免疫反应的基石。我们想要更好地了解C3a/C3aR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。我们想要识别相关的C3a依赖细胞，并描述C3a在这种情况下是如何发挥作用的。我们想要弄清楚细胞对C3a的直接反应有多远，以及其他表达C3aR的细胞有多大程度的间接影响(即释放不同的介质)。在这一背景下，我们想要阐明在细胞培养中CPS感染的肺上皮细胞如何合成和局部激活补体因子，以及粘膜细胞如何通过细胞因子与DC和T细胞相互作用。我们遵循不同的问题，旨在阐明补体和C3a/C3aR导致增强对细胞内细菌的保护的机制。我们将在这个模型中获得的许多详细结果很可能也适用于其他细胞内的肺部病原体，或导致亚急性-慢性病程的细胞外病原体。从长远来看，我们的结果可能有助于通过免疫调节改善肺部感染的结果，从而改善治疗效果。

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.