Infectious diseases are a leading cause of morbidity and mortality worldwide and are a major challenge for public health. Improved sanitary conditions, clean water supplies and vector control are the most effective measures to reduce the incidence of infectious diseases. However, particularly in the developed world, where the incidence of immunocompromised individuals rises, infections with opportunistic pathogens constitute an increasing problem. Besides bacterial and viral opportunistic pathogens, some fungi including Candida albicans, Aspergillus sp. and Pneumocystis jirovecii are of major clinical relevance. Although these fungal species establish stable host-parasite interactions, allowing host survival without parasite elimination in healthy individuals, they cause clinically relevant infection when host defenses are breached. This is for instance the case in neutropenic or T cell deficient individuals, in patients who have undergone transplantation, patients with various types of leukemia and people infected with HIV. The rising incidence of fungal infections and the increase of resistance against classical antifungal drugs necessitate the development of novel preventive and therapeutic strategies. For this however, a better understanding of microbial pathogenesis and the host immune response is indispensable.
Protection from fungal infections is critically dependent on the integration of both the innate and adaptive arm of the immune system. The innate immune system detects the presence of microbes by so-called pattern recognition receptors (PRRs) which allow the direct detection of conserved molecular signatures of potential pathogens (so-called ‘pathogen-associated molecular patterns’ or PAMPs). The best known PRRs are the Toll like receptors (TLRs) of which most signal via the common adaptor MyD88. They elicit direct antimicrobial responses in neutrophils and macrophages. In addition, TLR signaling in antigen-presenting cells such as dendritic cells leads to full activation of these cells characterized by expression of costimulatory molecules at the cell surface and secretion of proinflammatory cytokines. Dendritic cells equipped with these effector functions have the capacity to initiate T cell responses and thus to instruct adaptive immunity. A few non-TLR receptors have recently been identified to function as PRRs. One of those is Dectin-1, a member of the C-type lectin family that acts as receptor for fungi. As Salomé LeibundGut could show during her postdoc in the laboratory of Caetano Reis e Sousa (London), this receptor acts in an analogous manner to, but completely independently of TLRs. Dectin-1 is critical for immune recognition of fungi and for protection from fungal infection. The receptor is activated by the essential yeast cell wall component beta-(1,3)-glucan and signals via the kinase Syk. Dendritic cells stimulated through Dectin-1 adopt a fully activated state capable of inducing full blown CD4+ and CD8+ T cell responses as well as antibody production.
Salomé LeibundGut's past work has revealed important features of fungal recognition and immune activation. However, many questions regarding host defense against fungal pathogens remain unresolved. As evidenced by the increased prevalence of mycoses in AIDS patients, T helper cells play a pivotal role in combating fungal infections. Understanding the molecular and cellular events leading to T cell activation and function during fungal infections will thus be the main focus of her research. The principles of T cell activation that she discovered in a model system with isolated fungal determinants will be explored more globally in the context of infection with the clinically relevant fungal pathogen Candida albicans.
One part of the project will comprise an in depth characterization of Candida-specific T cells with respect to their effector functions and protective capacity. Moreover, the antigen-specificity of these T cells will be determined and T cell epitopes will be identified. Despite the large number of potential antigens available in each pathogen, T cell responses are usually restricted to a few epitopes. For most pathogens including fungi these epitopes remain unknown to date. A second part of the project will be devoted to the question how Candida-specific T cells are activated and how signaling via different PRR in dendritic cells impacts on this process. This will shed light on how the innate immune system regulates adaptive responses during fungal infections. Together, the data obtained from this research shall contribute to the understanding of basic principles of host-pathogen interactions and to the evaluation of protective principles during the course of infection with a clinically relevant pathogen. This may open up perspectives towards the development of novel preventive and therapeutic strategies for the reduction of morbidity and mortality associated with fungal diseases.
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