Lung interstitial macrophage remodeling during and after recovery from pneumococcal respiratory infection

Boston University Medical Campus, Boston MA

Investigators

Abstract

Project Summary Worldwide, acute lower respiratory tract infections, including pneumococcal pneumonia, are a major cause of mortality among all infectious diseases. Streptococcus pneumoniae continues to be the leading cause of bacterial pneumonia. Children under the age of two are repeatedly exposed to pneumococcus. These exposures result in naturally acquired heterotypic immunity. This immunity is protective in adult years, but eventually wanes with advanced age. The immune-mediated mechanisms of heterotypic protection remain incompletely understood. Past studies from our lab show that mediators of this protection are concentrated inside the recovered lung specifically, making it a major priority to understand lung-localized immune cells and activities. Multiple innate and adaptive immune cells of the lung are profoundly changed after recovery from pneumococcal infections. Alveolar macrophages (AM) in lungs of pneumococcus-experienced mice exhibit changes to more than one tenth of their transcriptome, have altered surface marker expression and metabolomes, and more faithfully resemble human AMs when acutely infected. In contrast, the remodeling and immune defense roles of lung interstitial macrophages (IMs) are underappreciated. IMs are becoming better defined, with two subsets (CD206+ and CD206-) found in the mouse lung. CD206+ IMs are posited to have pro-resolving and anti-inflammatory roles whereas CD206- IMs have genes associated with antigen presentation. Preliminary data shows both subsets are increased in the recovered lung, with CD206+ IMs having changes in surface marker expression and enhanced association with bacteria, suggesting a remodeled phenotype. Therefore, we hypothesize that the remodeled CD206+ IMs contribute to lung immune defense during and after recurrent pneumococcal exposures. This hypothesis will be tested through two specific aims: Aim 1) to test the hypothesis that experience remodels lung IMs, and Aim 2) to test the hypothesis that CD206+ IMs have different functional significance in the experienced lung. Advancing our fundamental understanding of IM phenotypes in the recovered lung, as well as their immune defense roles, will be useful for developing host-directed therapies and vaccine-elicited protection.