Role of STAT5 pathway in innate immune response during Aspergillosis – AspSTAT5

The incidence of invasive fungal infections on human health represents a major worldwide health burden accounting for more than 1 million attributed deaths a year. These deep-seated infections are associated with dramatic mortality rates that may be 20 to 50% in immunocompromised patients. Aspergillus fumigatus is one of these major fungal pathogens causing invasive pulmonary aspergillosis (IPA). For this reason, research to better understand A. fumigatus pathogenesis is essential for the development of new therapeutic strategies. The innate immune system developed a multitude of mechanisms to control infection. The pathogen-associated receptors (PRRs) as toll-like receptors (TLRs) and C-type lectin receptors (CLRs) recognize the fungus and mediate the innate immune response and cytokine release. The JAK/STAT pathway are an essential cellular signaling mechanism necessary to respond to cytokine and modulate the immune response to infection. The STATs induce the expression of hundreds of genes, which empower the cells against the insult. There are seven STATs, and the functional importance of STAT1 or STAT3 in the restriction of A. fumigatus infections is well defined. However, role of STAT5 in fungal infections is not understood and remains a mystery. The goal of this proposal is to elucidate and reveal the specific function of STAT5 during IPA. We propose to: 1) characterize and identify the regulatory mechanisms of STAT5 during Af infection of macrophages; 2) examine the role and functions of STAT5 during macrophage infection; and 3) characterize the role of STAT5 in the myeloid compartment during pulmonary aspergillosis. Finally, the benefit of this proposal will provide a clear understanding of STAT5 requirement during A. fumgiatus infection. It may contribute to the development of novel anti-fungal therapies but also against autoinflammatory diseases and cancer.