Innate control of the inflammatory process during fungal infections

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 DESCRIPTION (provided by applicant): Fungi usually infect the skin and mucosa. Healthy individuals can efficiently control such infections; however, in immunocompromised individuals and nosocomial patients, fungal infections may become systemic, at which point they are associated with significant morbidity. Candidiasis is the most common fungal infection, and is associated with prolonged hospital stays and high mortality rates. The premise underlying the proposed experiments is that understanding the mechanisms of activation of the inflammatory process that controls fungal infections in healthy individuals will reveal novel therapeutic target that can be used to treat candidiasis in susceptible patients. Here, we seek to uncover how activation of Nuclear Factor of Activated T cells (NFAT) in innate immune and non-immune cells induces protective immune responses against Candida, thus preventing invasive spread of the fungus and lethal systemic candidiasis. Inflammation is a protective vascular response to noxious stimuli that causes increased blood vessel permeability and recruitment of immune cells to the site of infection to combat the invading microorganism. Innate immune and tissue-specific non-immune cells regulate the development and potency of the inflammatory process via transcriptional and non-transcriptional responses, and lead to the formation of a protective adaptive immune memory. The NFAT family of transcription factors was originally associated with activation of adaptive immune cells; but we and others have demonstrated that the NFAT pathway is also potently activated in innate immune and non-immune cells following exposure to inflammatory stimuli, especially in response to fungal recognition. A major effect of NFAT activation is to induce a large increase in the production of prostaglandin (PG)E2 and interleukin (IL)-2, but the significance of the huge spike in the concentration of these molecules in response to fungi is totally unexplored. We aim to test the hypothesis that, in response to fungal infection NFAT is activated in innate immune and non-immune cells to regulate the inflammatory process, destruction of the invading pathogen, and formation of a protective memory. We will use mouse models to determine how early NFAT activation orchestrates fungal recognition and destruction, efficient transport of pathogen to the draining lymph node (dLN), and remodeling of LN microarchitecture (important for adaptive immune cell activation and long lasting protection) during anti-fungal inflammatory responses. This represents a new, unexplored area of investigation, with important implications for gaining insights into the complexity of inflammation driven immunity, and for addressing the excess mortality and the length and financial burden of hospitalization, which present a potent mandate for designing improved means of preventing and treating candidiasis in adults and children. We contend that clarification of the role of NFAT activation during the initial phases of the inflammatory process will provide a fundamental breakthrough for designing new strategies for treating fungal infection, and will yield a greater understanding of the physiology of inflammation.