Thursday, November 21, 2024
11/21/2024
GM-CSF, macrophages, and susceptibility to Mycobacterium abscessus pulmonary infection Nontuberculous mycobacteria (NTM) do not cause disease in healthy individuals; however, people with chronic airways diseases are susceptible to developing pulmonary NTM infections (pNTM), which increase symptom burden and accelerate lung function decline. How the healthy lung clears inhaled NTM and why individuals with airways disease are at increased risk of developing pNTM remain poorly understood. Our long term goal is to understand how macrophage heterogeneity contributes to chronic lung diseases. The objective of this grant is to characterize events that occur when inhaled NTM initially interact with respiratory tract macrophages, and determine how the cytokine granulocyte macrophage colony stimulating factor (GM-CSF) promotes clearance of NTM. Data from human case reports and mice lacking GM-CSF (GM-CSFKO mice) indicate that GM-CSF is essential for immune control of pNTM. We have chosen to study the role of GM-CSF in susceptibility to Mycobacterium abscessus (MAbsc) as this species causes a significant portion of pNTM, is increasing in prevalence, and is especially challenging to eradicate. Our data demonstrate that GM-CSF can activate macrophages to kill MAbsc. In lung airspaces, macrophages can be grouped into two main categories: resident alveolar macrophages (AlvMs) and recruited monocyte-derived macrophages (MDMs). AlvMs are constitutively exposed to GM-CSF produced by alveolar epithelial cells. In contrast, most macrophages in airways of people with chronic airways disease are MDMs recruited from the bloodstream, a compartment with low levels of GM- CSF. Our central hypothesis is that macrophages must be activated by GM-CSF to eliminate NTM, and that MDMs recruited to the airways in people with chronic airways disease are less effective at killing NTM than AlvMs due to insufficient exposure to GM-CSF. We will investigate this hypothesis in three specific aims. Aim 1 will determine the mechanism by which GM-CSF enhances macrophage killing of MAbsc, testing the hypothesis that GM-CSF promotes phagosomal maturation and phagolysosomal acidification. Using conditional knockout mice that lack the GM-CSF receptor on different macrophage subsets, Aim 2 will test the hypothesis that resident AlvMs programmed by GM-CSF are the essential cells responsible for control of MAbsc in the healthy lung. Aim 3 will employ a mouse model of airway infection using MAbsc-embedded agar beads to test the hypothesis that there is insufficient GM-CSF in the airways to activate recruited MDMs to develop mycobacteriocidal phenotypes. These studies are innovative, as they will determine the mechanisms by which GM-CSF enhances macrophage killing of MAbsc, and reveal how location in the lung influences phenotypes of recruited MDMs. The results from the proposed research will be significant, as they will inform use of immune therapies to treat non-resolving infection in chronic lung diseases, and they could help predict which individuals with chronic lung diseases are at highest risk for developing pNTM.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
