Advisory Committee Chair
Claude H Steele, Iii
Advisory Committee Members
Robin D Hatton
Louis B Justement
Alexander J Szalai
Hubert M Tse
Document Type
Dissertation
Date of Award
2012
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Pneumonia caused by the fungal pathogen Pneumocystis continues to be the leading cause of morbidity and mortality in AIDS patients. In addition, there are a number of other non-HIV-associated diseases that render an individual susceptible to Pneumocystis infection, including chronic obstructive pulmonary disease. Innate immune mechanisms are important for controlling Pneumocystis lung infection. As alveolar macrophages serve the front lines of lung host defense, our goal was to elucidate their responses during lung Pneumocystis infection. Here, we established a role for Src family kinases in the lung immune response to Pneumocystis, which uncovered a role for alternatively activated alveolar macrophages. In addition, alveolar macrophages, when polarized toward alternative activation, are able to effectively kill Pneumocystis in vitro. We further identified the IL-1 family member, IL-33, as a potent effector molecule against Pneumocystis via the enhancement of alternative macrophage activation in experimental Pneumocystis infection. Although alveolar macrophages are thought to be the primary innate immune effector cell during Pneumocystis lung infection, we also identified eosinophils as a potent effector cell type. We showed that mice deficient for eosinophils have increased susceptibility to experimental Pneumocystis infection. Subsequently, we showed that eosinophils generated in vitro from mouse bone marrow are capable of directly killing Pneumocystis in vitro. In a bedside-to-bench translational approach, we also explored colonization mechanisms potentially linking Pneumocystis infection to exacerbations during chronic obstructive pulmonary disease. Ultimately, we hypothesized that alternatively activated macrophages and eosinophils participate in innate immune responses to Pneumocystis and the interplay between Pneumocystis and the host immune response plays a role in exacerbating chronic obstructive pulmonary disease.
Recommended Citation
Nelson, Michael Paul, "Innate Immune Mechanisms against the Atypical Fungal Pathogen Pneumocystis murina" (2012). All ETDs from UAB. 2566.
https://digitalcommons.library.uab.edu/etd-collection/2566