Dysregulated iron metabolism shapes alveolar macrophage response to Streptococcus pneumoniae in copd

The necessity of iron as an enzymatic cofactor for metabolic reactions in both mammalian and microbial cells positions it as a key mediator of host-pathogen interactions, where the ‘fight for iron’ is a crucial determinant in the ability of pathogens to survive and replicate in the host. Systemically, macrophages are central in iron recycling and handling, but the effects of altered macrophage iron levels on infection outcomes are not fully understood. In chronic obstructive pulmonary disease (COPD), lung-resident alveolar macrophages (AMs) are iron loaded, and the abundance of iron in the extracellular milieu correlates with more frequent infection-driven exacerbation events.  While such exacerbations are a large cause of morbidity and mortality in COPD, how macrophage iron loading affects host-pathogen interactions in the lung is poorly understood.



Here we show that in vitro and ex vivo, murine AMs subjected to experimental COPD have higher total and mitochondrial iron, confirmed through graphite furnace-atomic absorption spectrometry, confocal microscopy, and qPCR/western blotting of factors governing cellular iron metabolism. These “COPD” macrophages are more susceptible to infection with Streptococcus pneumoniae, a common respiratory pathogen in COPD, assessed by ELISA (IL-6, TNF-α and lipocalin-2) and enumeration of intracellular colony forming units (CFU). The sensitivity of S. pneumoniae intracellular replication to host iron levels was also demonstrated through CFU enumeration in murine AMs pre-treated with iron or iron chelators. These results highlight the role of dysfunctional iron metabolism in promoting bacterial virulence and suggest the targeted manipulation of macrophage iron as a novel therapeutic avenue in COPD.