InnateFun: Stimulating Antifungal Innate Immunity

According to the WHO, infectious diseases stand out as the major cause of death. While bacterial, viral and parasitic infections constitute the major threat, the clinical relevance of fungal infections has not been adequately recognized. In fact, invasive fungal infections constitute a biomedical problem of epic proportions, since a handful of human fungal pathogens claim an estimated 1.5 million lives per year. Fungal diseases constitute a leading cause of morbidity and mortality for hospitalized individuals, particularly in patients with haematological malignancies, bone-marrow and organ transplant recipients, intensive care unit patients, preterm neonates, and patients with inborn immune disorders such as AIDS. Of note, accurate clinical diagnosis and a limited arsenal of antifungal drugs pose challenging problems in the therapy of fungal infections. Currently, existing antifungal treatments exclusively attempt to block fungal pathogens in the host. By contrast, the central idea of InnateFun is to decipher the molecular mechanisms of innate immune surveillance, which could be useful for therapeutic interventions to better treat invasive fungal infections. The major hypothesis of InnateFun is that pharmacological modulation of the host inflammatory response by specific activators or inhibitors of fungal pattern receptors can provide novel therapeutic options for Candida spp infections. Hence, InnateFun will develop novel drugs supporting host immune surveillance to better recognize and clear invasive fungal infections. Partner Karl Kuchler will be testing the activities of novel lead immune-modulatory compounds (IMCs). The IMCs will be developed through an iterative cycle of computer-aided rationale drug design, chemical synthesis and experimental optimization in vitro using native immune cells but also immuen cells from patients with altered susceptibility to fungal infections. Immune cells such as macrophage killer cells, so-caelled dendritic cells and white blood cells, the key innate immune cells required for fungal clearence, will be used for drug testing. Wes hall employ immunological readouts such as cytokine signaling signatures, and the inflammatory response mediated by interleukins and other cytokines. A maximum of two-three IMCs of high antifungal activity in vitro, will be subjected to in vivo testing using mouse models of invasive candidiasis. The seamless cooperation between academic, clinical and industrial partners will facilitate the translation of IMCs drugs into clinical applications. Finally, and most importantly, we expect to successfully identify new chemical entities of antifungal leads IMCs. Hence, InnateFun shall establish a proof-of-principle for novel antifungal drugs that interfere with the host immune response rather than fungal growth, and thus yield a deeper understanding of the molecular basis of host immune surveillance and host-fungal interactions.

According to the WHO, infectious diseases stand out as the major cause of death. While bacterial, viral and parasitic infections constitute the major threat, the clinical relevance of fungal infections has not been adequately recognized. In fact, invasive fungal infections constitute a biomedical problem of epic proportions, since a handful of human fungal pathogens claim an estimated 1.5 million lives per year. Fungal diseases constitute a leading cause of morbidity and mortality for hospitalized individuals, particularly in patients with haematological malignancies, bone-marrow and organ transplant recipients, intensive care unit patients, preterm neonates, and patients with inborn immune disorders such as AIDS. Of note, accurate clinical diagnosis and a limited arsenal of antifungal drugs pose challenging problems in the therapy of fungal infections. Currently, existing antifungal treatments exclusively attempt to block fungal pathogens in the host. By contrast, the central idea of InnateFun is to decipher the molecular mechanisms of innate immune surveillance, which could be useful for therapeutic interventions to better treat invasive fungal infections. The major hypothesis of InnateFun is that pharmacological modulation of the host inflammatory response by specific activators or inhibitors of fungal pattern receptors can provide novel therapeutic options for Candida spp infections. Hence, InnateFun has develop compounds boosting host immune surveillance to better clear invasive fungal infections. Partner Karl Kuchler has been testing the activities of such novel lead immune- modulatory compounds (IMCs). The IMCs were developed through iterative cycles of computer-aided rationale drug design, chemical synthesis and experimental optimization in vitro using native immune cells from mouse models with altered susceptibility to fungal infections. Immune cells such as macrophages, so-called dendritic cells and white blood cells, the key innate immune cells required for fungal clearence, were used for drug testing. The research employed immunological readouts such as cytokine signaling signatures, and the inflammatory response mediated by interleukins and other cytokines, as well as mechanisms by which immune signaling affected the regulation of metal ion homeostasis and fungal virulence. Two IMCs of high antifungal activity were tested in vitro and in vivo using mouse models of invasive candidiasis. The key results of the project established that IMC immunomodulatory compounds can in principle be used for the treatment of invasive fungal infections. This proof-of-principle requires additional validation and translation to human infection settings. Furthermore, a surprising and unexpected outcome revaled a tight mechanistic link of interferon immune responses in that the group discovered new mechanisms how metal ion homeostasis (iron and zinc) is connected with a single immune signalingin innate immune cells. This cross-talk is amenable to establishing new therapeutic approaches for better treatment of invasive fungal infections by interfgering with metal ion homeostasis in either the host of the pathogen.