SFB TR 124, Project A2: Interaction of A. fumigatus with human NK cells, dendritic cells and human alveolar epithelia

SFB TR 124

In contrast to most bacterial pathogens, A. fumigatus goes through major morphological changes during the early phase of infection, resulting in different fungal surface structures. Cells of the innate immune system recognize the fungus and its different morphologies by distinct „Pattern-Recognition-Receptors“(PRR), which induce cell specific as well as general defense mechanisms. The most important cells of the initial innate immune system are alveolar epithelia, alveolar macrophages, as well as dendritic cells (DC). However, increasing data suggest the interaction of additional innate immune effector cells, such as natural killer cells (NK-cells) with the fungus. During invasion of the fungus into the blood vessels and its hematogenous dissemination, neither the different lines of host defense nor the influence of the inflammatory background of patient are very well characterized.

This project aims to systematically and comprehensively characterize the function of different lines of defense (involving DC sub- populations, alveolar epithelia, NK cells) against A. fumigatus in healthy individuals as well as in immunocompromised patients and to identify factors (immunosuppression, genetic factors, interaction with other effectors of the innate as well as of the adaptive immune system) that promote or interfere with the antifungal activity of innate immune effector cells. For this purpose, we will study the interplay of immune cells from healthy (and later from immunosuppressed donors) with different fungal morphotypes, focusing on receptor-ligand interactions, the mode of action of the involved innate immune cell populations as well as the signaling pathways induced by this interaction. Running parallel experiments with different species of fungi, A. fumigatus and Candida albicans,  and by performing comparative analyses of the respective human and fungal transcriptomes, we will identify genes, especially immune response genes, which are either cell-type specifically regulated or similarly regulated in different cells of the innate immune system (epithelia, DCs, NK, cells).

Therefore, we will identify genetic markers in these candidate genes, which are potentially associated with a higher risk to develop IA. In addition, we will study the cross talk between distinct innate immune effector cells and investigate by which means this interaction modulates the response towards A. fumigatus. In the last part of this project, based on the findings of the functional analyses of DCs and NK cells towards A. fumigatus, we will develop GMP-grade protocols for the generation of DCs and NK cells suitable for clinical use.