Aspergillus fumigatus is a ubiquitous airborne fungus that causes severe invasive disease in immunocompromised patients. Invasive aspergillosis (IA) is a devastating disease characterized by a high mortality rate and rapid progression to death, despite aggressive treatment with anti-fungal agents. Due to the increasing prevalence and severity of IA, more effective treatment strategies are critically needed. T lymphocytes are thought to play an important role in protective immunity against Aspergillus. Recent studies using murine models have shown that the establishment of a Th1-type cytokine environment is associated with protection against IA, while the development of predominantly Th2-type cytokines correlates with invasive disease and lethality. However, the precise role of T lymphocytes in protection against and recovery from IA is not well defined. The experiments proposed in this study will focus on the generation and characterization of Th1-type Aspergillus-specific CD4+ T lymphocytes, and the capacity of these cells to provide protection against lethal A. fumigatus infection upon transfer into naive animals. We will also analyze the trafficking and antigen-specific expansion of the transferred cells following antigenic challenge. In addition, we will investigate the role of the Toll-like receptor pathways and the balance between the innate and adaptive immune responses in the context of Aspergillus infection.
