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

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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.