IL-17-producing innate cells in fungal infections

Out of thousands of fungal species present around the globe, only a few are capable of causing disease in humans. However, in the rare situations where they cause pathological situations, fungal infections bear serious health hazards and are associated with high mortality rates as they predominantly develop in patients with suppressed immunity. The fact that until today no vaccine against any fungal pathogen is available highlights the necessity of better understanding the physiological interaction between host and fungal pathogen to develop rational therapeutic approaches. Candida albicans is one of the most clinically relevant fungal organisms, as it can cause a variety of diseases ranging from superficial infections of the skin and the mucosa, to severe systemic infections. In recent years, interleukin-17 (IL-17)-mediated immunity has emerged as a crucial host defense mechanism against fungal infections. Individuals with rare genetic mutations in genes associated with the IL-17 pathway are highly susceptible to fungal infections, in particular mucocutaneous infections with Candida albicans, illustrating the non-redundant role of IL-17 in antifungal immunity. However, the detailed mechanism underlying protection from infection remains largely unclear. T helper cells (so-called Th17 cells) are generally believed to act as the principal mediators of IL-17 immunity against fungi. However, for effective fungal control IL-17 is required right from the onset of infection, long before T helper cells become functional. It has now become clear that the recently identified population of innate lymphoid cells (ILCs) act as the critical early source of IL-17 and that this population of cells is essential and sufficient for IL-17-mediated protective immunity, in particular at barrier tissues. While cytokine production by T helper cells has been studied in much detail, the regulation of IL-17 secretion by ILCs is not well understood. Although the cytokine IL-23 has been proposed to be involved in this process, the source and regulation of this ILC-activating factor is uncertain, as well as the contribution of additional or alternative factors. Here I propose to study the cellular and molecular mechanism underlying IL-17-mediated protective immunity during fungal infection. Using a mouse model of mucosal infection with Candida albicans (oropharyngeal candididasis), I will investigate the IL-23-dependent and independent events during infection and identify accessory cells and the signaling molecules involved in the control of IL-17 production during the acute antifungal response. This important project will help elucidating the complex host-pathogen interactions that critically decide right at the onset of infection whether the pathogen prevails or whether it is controlled by the host. The gain in knowledge shall provide important new perspectives for the future development of novel therapeutic strategies.

Candida albicans is part of the healthy microflora of humans but can cause various diseases in hosts with a weakened immune system. These pathologies include infections of the mucosa and the skin as well as severe blood stream infections. Interleukin-17 (IL-17) has emerged as key cytokine for protective immunity against C. albicans-mediated infections at the barrier tissues. This notion is supported by the fact that mutations in genes associated with IL-17 signaling render humans highly susceptible towards mucocutaneous Candida infection. Consistently, experiments with mouse models for oral Candida infection demonstrated that protective immunity in those animals critically depends on the production of IL-17 rapidly after onset of infection.However, little was known about the type of cells that produce IL-17 and how IL-17 production is regulated in the mucosal tissue during the course of the disease. Using a mouse model for oral C. albicans infection this project aimed on characterizing in detail the IL-17-producing cells in the infected mucosa and further investigate the underlying molecular mechanism that regulates IL-17 production during the acute phase of infection. To do so we established a new method that allowed us for the first time to visualize IL-17 protein production on a single cell level in the infected tissue. We could demonstrate that IL-17 is produced by a heterogeneous population of leukocytes comprising ?? and ?? T cells as well as innate lymphocytes shortly after onset of infection. IL-17 production by those leukocytes relies on at least three instructive cytokines including IL-23, IL-1 and IL-6. In search for the cellular source of those IL-17-instructing cytokines we could show that IL-6 and IL-1 is predominantly produced by phagocytes of the mucosal tissue, which prompted us to further characterize this cell population in more detail. We finally could show that phagocytes in the tongue consist of Macrophages and Langerin Dendritic cells whereby the latter ones are crucial for the regulation of IL-17 production since they secrete large amounts of IL-1 and IL-6 during oral C. albicans infection. In summary, our work describes so far unknown immunological events that occur in the infected mucosa during acute phase of oral C. albicans infection. Our results shall provide the basis for the development of novel and urgently needed therapeutic approaches in order to treat these diseases. In addition, the resulting knowledge about basic principles of IL-17 immunity in the context of infection will hopefully be translated to other diseases, in which IL-17 has pathological consequences promoting auto-inflammatory diseases, thereby leading to a better understanding and subsequent improved treatment of these ailments.