This proposal outlines a five-year training program for Dr. Cagnina to establish a career as an independent investigator in Pulmonary and Critical Care Medicine. Under the guidance of co-mentors Drs. Borna Mehrad and Tom Braciale, our broad, long-term objective is for Dr. Cagnina to gain new the knowledge and skills necessary to evolve into an independent physician-scientist, while making significant contributions to understanding the immune response to Aspergillus. Aspergillus species are ubiquitous molds that cause clinical disease in hosts with impaired immunity or abnormal mucosal defenses. Neutrophils play a key role in host defenses against this pathogen but little is known about the contribution of these cells in in this context beyond their direct microbicidal role. We have previously shown that, during host response to Aspergillus in the lung, neutropenia results in a defect in the traffic and maturation of inflammatory monocyte-derived dendritic cells. In the preliminary data for this proposal, we report that deficiency in neutrophil reactive oxygen species production is sufficient to induce this phenotype; that, in hosts unable to generate reactive oxygen species, both the inflammatory dendritic cell recruitment and lung injury are dependent on TNF; and that neutropenia impairs the development of protective immunity against the pathogen. We therefore seek to test the hypothesis that in response to Aspergillus, reactive oxygen species-dependent neutrophil signaling to inflammatory dendritic cells mediates (a) protection from acute lung injury and (b) generation of protective adaptive immunity against Aspergillus. We will test this under two specific aims: (1) To identify the mechanism by which neutrophil-derived ROS modulates dendritic cell function during the innate immune response to Aspergillus and (2) To define the role of neutrophil ROS in the development of protective adaptive immunity against Aspergillus. The proposed studies are relevant to public health by defining a new mechanism of host defense against an important human pathogen that should allow for future development of novel therapeutics or preventative strategies.

Public Health Relevance

Aspergillus is an environmental fungus that can cause several lung diseases including invasive aspergillosis, a dangerous infection in patients with weakened immunity. We seek to understand the components of the immune system that help the body fend off this infection. This knowledge has the potential to lead to new treatments to protect patients from this devastating infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08HL136903-03
Application #
9843337
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Kalantari, Roya
Project Start
2017-05-03
Project End
2022-04-30
Budget Start
2019-05-08
Budget End
2020-04-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115