Neutrophils and adaptive immunity against invasive aspergillosis

University Of Virginia, Charlottesville VA

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Abstract

? DESCRIPTION (provided by applicant): Invasive aspergillosis is a common fungal infection in immunocompromised patients and carries a poor prognosis. A thorough understanding of the components of the immune response to invasive aspergillosis in the context of immunocompromised hosts is important, because it may lead to the development of new treatments aimed at improving the host defense against this infection. Prior literature has documented that normal hosts are capable of generating a robust and protective adaptive immune response against Aspergillus, yet invasive aspergillosis often recurs in neutropenic hosts, suggesting that these hosts fail to generate protective immunity against the organism during the initial infection. In this context, we have previously established that neutropenic host have a defect in CD11b+ dendritic cell maturation and traffic after intrapulmonary challenge with Aspergillus. In the preliminary data for this proposal, we report that neutropenia during an initia challenge with Aspergillus results in failure to generate protective immunity against a subsequent infection and that mice deficient in the gp91phox component of NADPH oxidase complex develop a similar dendritic cell phenotype to neutropenic animals. We therefore hypothesize that neutrophils are necessary for the generation of protective adaptive immunity against invasive aspergillosis. We propose to test this hypothesis under the following specific aims: 1) To identify the contribution of neutrophils to the development of protective adaptive immunity against invasive aspergillosis; and 2) To define the role of neutrophil oxidative burst in generation of dendritic cell-mediated protective adaptive immunity to Aspergillus. We propose to use both novel and established animal models and in vivo cell depletion and adoptive transfer strategies to achieve these goals. The proposed studies are relevant to public health in that they should de- fine a novel host defense mechanism in an important human illness, with the prospect that this mechanism could be manipulated therapeutically to benefit patients.