The incidence of opportunistic fungal infections caused in particular by Aspergillus fumigatus and Candida species has increased over the last decades. These infections have earlier been a leading cause of morbidity and mortality in patients with HIV/AIDS and have now become most prevalent in patients suffering from leukemia and in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), solid organ transplantation (SOT) or immunosuppressive treatment^1,2. Despite antifungal prophylaxis or treatment, the therapeutic efficacy is often limited due to impaired host immunity, difficulties encountered in rapid and accurate diagnosis, emergence of uncommon or resistant pathogens, drug interactions and toxicity². Hence, specific immunological markers that predict development and outcome as well as alternative treatment approaches that could restore or boost fungus-specific immunity would be desirable for these patients. Adoptive T-cell therapy for fungal infections is promising but little is known regarding the protective immune response in humans³. In mice, distinct CD4⁺ T-helper (T_H) subsets are important for host responses against fungi. Coordinated activation of T_H1 immunity, regulatory T cells and probably T_H17 cells seems to be necessary for pathogen control by enhancing the innate immune cells, whereas activation of T_H2 cells often exacerbates disease^4,5. Therefore, understanding the mechanisms enhancing protective and/or dampening counteractive T_H subsets may help to prevent or treat local and disseminated fungal infections in humans, which is particularly important in the development of immunotherapeutic approaches such as adoptive T-cell therapy or when identifying immunomodulatory compounds^6,7. Although the time course of recovery of normal numbers of immune cells is well known for HSCT recipients or HIV-infected patients receiving antiretroviral therapy⁸, only little is known regarding possible qualitative impairments and the kinetics of recovery of the different fungus-specific T_H subsets as well as the interaction of fungus-specific adaptive immunity with the cells of the innate immune system. As we have previously identified a T-cell epitope stimulating cross-reactive T cells that recognize A. fumigatus as well as C. albicans, we are able by using a MHC class II tetramer to directly monitor and track the recovery of these epitope-specific T cells in patients suffering from A. fumigatus or C. albicans infections and correlate it with clinical outcome^9,10.

Aims

We aim to identify parameters of the antifungal immune response that correlate with the risk for developing invasive fungal infections (IFI) and/or the outcome of these infections. Further, we aim to increase and/or regulate antifungal T-cell immunity in immunocompromised patients either by adoptive transfer of fungus-specific T cells or by immunomodulatory compounds such as antifungal drugs, statins or vitamin D. Therefore, we need to characterise the different T_H subsets involved in antifungal defence as well as their interaction with innate immunity in patients with disease compared to unaffected patients and healthy donors.

Aim 1        To characterize the different T_H subsets specific for A. fumigatus and C. albicans in healthy donors, their interplay with each other and with cells of the innate immune system as well as their ability to be modulated by different compounds.

Aim 2        To identify qualitative and quantitative impairments of different T_H subsets and/or innate immunity in HSCT recipients with IA in a nested unmatched case-control study.

Aim 3        To assess qualitative and quantitative impairments of different T_H subsets in HIV-infected patients with Candida esophagitis in a CD4⁺ T-cell matched nested case-control study.

Relevance

The current antifungal treatments are associated with high costs and yet with unsatisfactory outcome. Therefore, specific immunological parameters that influence outcome or correlate with the risk for developing IFI are of great interest to optimize treatment duration or to identify the need for prophylaxis. The development of anti-infective immunotherapeutic strategies is still at a very early stage and we hope and are confidential to make a valuable contribution in the understanding of the plasticity as well as cross-talk between different antigen-specific immune cells that have to be taken into consideration for successful intervention. The results of this study should provide the rational for immunomodulatory and immunotherapeutic strategies in patients at risk for IFI, which could complement or replace conventional antifungal therapy.