Aspergillus fumigatus is a filamentous fungus that currently accounts for a majority of infection-related mortality in immunocompromised patients. The pulmonary response to inhaled Aspergillus fumigatus is mediated by the alveolar macrophage, which ingests and kills conidia before the spores have a chance to mature into hyphae. Macrophages coordinate secondary responses through mechanisms that include secretion of cytokines and chemokines, whilst dendritic cells (DCs) coordinate CD4+ T lymphocyte responses. Such responses have been characterized as both beneficial (Th1), and potentially harmful, with a predominant Th2-type phenotype associated with hypersensitivity lung disease. Recent studies have implicated Toll-like receptors in mediating multiple functions of innate and adaptive immunity, both by triggering macrophage secretion of soluble factors and by inducing DC maturation. Our studies indicate that A. fumigatus hyphal products stimulate macrophages to produce TNF-alpha and IL-6, and induce DCs to mature and prime Th1-type CD4+ T cells more than conidial products. Murine macrophage cytokine secretion in response to live fungi occurs independent of the pathway most frequently involved in signaling of TLR-mediated responses (MyD88), while heat-killed hyphal products stimulate cytokine secretion through a MyD88-dependent pathway. Live hyphal products also induce macrophage apoptosis, while conidia do not. To understand how these inflammatory responses to A. fumigatus are coordinated, three specific aims are proposed.
Specific Aim 1 will identify the inflammatory components of A. fumigatus hyphal preparations by screening polysaccharide, mannoprotein, and glycolipid cellular fractions for stimulatory activity in macrophage cell lines.
In Specific Aim 2, the role(s) of TLRs in mediating responses will be determined, using macrophages harvested from null mice.
Specific Aim 3 will test the hypothesis that MyD88-independent inflammatory responses may be coupled to apoptosis. This proposal utilizes a unique collaboration between specialists in mycology, and innate and adaptive immunity to approach the long-term goal of defining how the immune response to A. fumigatus is coordinated. As this organism is a model lung commensal and pathogen, knowledge generated from these studies will also increase our understanding of mechanisms of specificity of innate host defense.
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