Role of iron in the pathogenesis of respiratory disease

Abstract

Iron is essential for many biological processes, however, too much or too little iron can result in a wide variety of pathological consequences, depending on the organ system, tissue or cell type affected. In order to reduce pathogenesis, iron levels are tightly controlled in throughout the body by regulatory systems that control iron absorption, systemic transport and cellular uptake and storage. Altered iron levels and/or dysregulated homeostasis have been associated with several lung diseases, including chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. However, the mechanisms that underpin these associations and whether iron plays a key role in the pathogenesis of lung disease are yet to be fully elucidated. Furthermore, in order to survive and replicate, pathogenic micro-organisms have evolved strategies to source host iron, including freeing iron from cells and proteins that store and transport iron. To counter these microbial strategies, mammals have evolved immune-mediated defence mechanisms that reduce iron availability to pathogens. This interplay between iron, infection and immunity has important ramifications for the pathogenesis and management of human respiratory infections and diseases. An increased understanding of the role that iron plays in the pathogenesis of lung disease and respiratory infections may help inform novel therapeutic strategies. Here we review the clinical and experimental evidence that highlights the potential importance of iron in respiratory diseases and infections.

Moonlighting of Haemophilus influenzae heme acquisition systems contributes to the host airway-pathogen interplay in a coordinated manner

“…The need of invading bacteria to acquire nutrient metals from their environments has caused vertebrate hosts to evolve to restrict their bioavailability. Nutrient iron sequestration is one mode of innate defence termed "iron nutritional immunity", whereby iron levels are tightly controlled by host regulatory systems controlling its absorption, systemic transport, distribution, cellular uptake, and storage [1,2]. In response to this, pathogens evolve mechanisms of host iron piracy to scavenge this metal during infection [3].…”

“…Moreover, alveolar hemorrhaging observed in several lung disease conditions leads to increased iron levels. As a consequence, strong evidence for dysregulated iron homeostasis exists in major respiratory diseases including chronic obstructive pulmonary disease (COPD) [1,2,[13][14][15]. COPD is a complex progressive condition characterized by chronic airway inflammation, associated with airway remodeling, alveolar destruction and persistent airflow obstruction [16].…”

In VitroProbiotic Potential of Hemophilin-producing Strains ofHaemophilus haemolyticus

“…For commensals and pathogens living in or invading human tissues, iron-containing heme is often a limiting nutrient, particularly in the respiratory tract where concentrations are considered to be low (44). This is particularly true for heme auxotrophs including NTHi and Hh; for these species survival in the URT niche is dependent on their ability to outcompete host proteins and co-existing bacterial populations for heme (20).…”

“…We previously demonstrated that the NTHi-inhibitory mechanism of HPL is associated with it’s ability to bind heme in a form inaccessible to NTHi and that inhibitory activity is lost in conditions where heme concentration exceeds the binding capacity of HPL (29). While levels of heme/iron are considered to be low in the respiratory tract, there is indirect evidence for increased heme/iron levels in airways of smokers, COPD and CF which may contribute to increased susceptibility to infection in these individuals (44). Thus, it was important to assess the effectiveness of HPL with varying concentrations of heme to ensure probiotic effectiveness in a range of in vitro conditions reflecting possible in vivo scenarios.…”

“…The NTHi-inhibitory capacity of HPL was maintained even in conditions of high heme-availability (15 μg mL −1 ), albeit to a lesser degree than lower heme concentrations (0.0-3.8 μg/mL) (Figure 1A). This suggests that levels of HPL produced by Hh are sufficient to limit NTHi’s access to heme in a dynamic in vitro system, even under excess heme conditions unlikely to be encountered in vivo (44).…”