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.

Public Health Relevance

Invasive pulmonary aspergillosis is an common infection in patients with weakened immunity. Many of the patients who catch this infection die of it despite receiving the best available treatment. We want to understand the components of the immune system that help fight off this infection. The goal is to use this information to develop new treatments to strengthen the immune response to this infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI117397-02
Application #
8996132
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Duncan, Rory A
Project Start
2015-02-01
Project End
2017-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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