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The LeibundGut Lab - Host Protection from Fungal Infections

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Infectious diseases caused by fungal pathogens represent a major health hazard for immunocompromised individuals. The incidence of fungal infections has risen continuously in recent decades due to the increase in immunosuppression as a consequence of modern medicine and the HIV pandemic. Despite this pressing need for novel preventive and therapeutic strategies research on fungal pathogenesis and antifungal host defense remains largely neglected. Our work aims at elucidating the cellular and molecular mechanisms of host protection from fungal infections. The main interest of our group is to understand host-protective mechanisms against this important class of infections. We focus in particular on interleukin 17, a cytokine that has emerged as a key component in antifungal defense.

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Portrait of the LeibundGut Lab »»

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Research areas:

Fungal infections

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 such as Candida albicans 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. Invasive candidiasis ranks among the four most frequent nosocomial infections and is most often a consequence of general immunosuppression, prolonged treatment with antibiotics or breaches in anatomical barriers (e.g. surgery or central venous catheter). It is associated with a mortality of more than 30% and a high morbidity in those who survive. Other forms of candidiasis are less severe, including superficial infections of the skin, the oropharyngeal mucosa and the vagina. These diseases are often associated with defects in cellular immunity but they can also occur in individuals that have no obviously weakened immune system. Although mucocutaneous Candida infections are not themselves life-threatening, they constrict the patient's quality of life severely. The increasing incidence of resistance to antifungal drugs and an inherent drug tolerance of some fungi cause major obstacles to an efficient treatment. This situation evokes an urgent need for the development of novel therapeutic approaches against fungal infections and has renewed the interest in the development of vaccination strategies against mycoses. This however requires a thorough knowledge of the immune response that clears or controls the infecting fungi.

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Interleukin-17

Interleukin-17 (IL-17)-mediated immunity has emerged as a crucial host defense mechanism against fungal infections. Allelic variations in genes of the IL-17 pathway have recently been linked with fungal diseases, in particular chronic mucocutaneous candidiasis. IL-17 also plays a central role for protective antifungal immunity in mice. Defects in IL-17 production or function render mice unable to control mucosal and cutaneous infections or systemic dissemination of C. albicans. In addition to its beneficial role in the context of fungal infections, IL-17 has a high pathogenic potential: it can promote inflammatory diseases such as psoriasis and inflammatory bowel disease and is involved in the pathogenesis of autoimmunity.

T helper cells produce IL-17 and are thus widely accepted as the key players of protective antifungal immunity. Indeed, fungi drive the differentiation of T cells into Th17 cells, and C. albicans-specific T cells present in the peripheral blood of healthy individuals belong preferentially to this subset. However, other cellular sources may also contribute to the IL-17 response to C. albicans. Little remains known on the regulation of IL-17 immunity during fungal infection. Our research aims at investigating the cellular and molecular mechanism of IL-17 induction by and IL-17-mediated protection from mucosal and systemic infection with C. albicans. The resulting gain in knowledge shall contribute to the better understanding of basic principles of host-pathogen interactions and to the evaluation of protective principles. 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. A better understanding of the IL-17 pathway may however also provide insights into why IL-17-mediated immunity can have detrimental effects in some cases causing pathology and auto-inflammatory disease.

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Using different mouse models of fungal infection our group aims at understanding IL-17-mediated host defense mechanisms that confer protection from mucosal (oropharyngeal) and systemic candidiasis.

Projects of the LeibundGut Lab »»

 

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© 2014 Microbiology ETH Zürich | Imprint | Disclaimer | 5 June 2013
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