Hepcidin and Host Defense against Infectious Diseases.

Hepcidin is the master regulator of iron homeostasis in vertebrates. The synthesis of hepcidin is induced by systemic iron levels and by inflammatory stimuli. While the role of hepcidin in iron regulation is well established, its contribution to host defense is emerging as complex and multifaceted. In this review, we summarize the literature on the role of hepcidin as a mediator of antimicrobial immunity. Hepcidin induction during infection causes depletion of extracellular iron, which is thought to be a general defense mechanism against many infections by withholding iron from invading pathogens. Conversely, by promoting iron sequestration in macrophages, hepcidin may be detrimental to cellular defense against certain intracellular infections, although critical in vivo studies are needed to confirm this concept. It is not yet clear whether hepcidin exerts any iron-independent effects on host defenses

A computational model of invasive aspergillosis in the lung and the role of iron

BACKGROUND: Invasive aspergillosis is a severe infection of immunocompromised hosts, caused by the inhalation of the spores of the ubiquitous environmental molds of the Aspergillus genus. The innate immune response in this infection entails a series of complex and inter-related interactions between multiple recruited and resident cell populations with each other and with the fungal cell; in particular, iron is critical for fungal growth. RESULTS: A computational model of invasive aspergillosis is presented here; the model can be used as a rational hypothesis-generating tool to investigate host responses to this infection. Using a combination of laboratory data and published literature, an in silico model of a section of lung tissue was generated that includes an alveolar duct, adjacent capillaries, and surrounding lung parenchyma. The three-dimensional agent-based model integrates temporal events in fungal cells, epithelial cells, monocytes, and neutrophils after inhalation of spores with cellular dynamics at the tissue level, comprising part of the innate immune response. Iron levels in the blood and tissue play a key role in the fungus’ ability to grow, and the model includes iron recruitment and consumption by the different types of cells included. Parameter sensitivity analysis suggests the model is robust with respect to unvalidated parameters, and thus is a viable tool for an in silico investigation of invasive aspergillosis. CONCLUSIONS: Using laboratory data from a mouse model of invasive aspergillosis in the context of transient neutropenia as validation, the model predicted qualitatively similar time course changes in fungal burden, monocyte and neutrophil populations, and tissue iron levels. This model lays the groundwork for a multi-scale dynamic mathematical model of the immune response to Aspergillus species. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-016-0275-2) contains supplementary material, which is available to authorized users

Hepcidin and Host Defense against Infectious Diseases.

Hepcidin is the master regulator of iron homeostasis in vertebrates. The synthesis of hepcidin is induced by systemic iron levels and by inflammatory stimuli. While the role of hepcidin in iron regulation is well established, its contribution to host defense is emerging as complex and multifaceted. In this review, we summarize the literature on the role of hepcidin as a mediator of antimicrobial immunity. Hepcidin induction during infection causes depletion of extracellular iron, which is thought to be a general defense mechanism against many infections by withholding iron from invading pathogens. Conversely, by promoting iron sequestration in macrophages, hepcidin may be detrimental to cellular defense against certain intracellular infections, although critical in vivo studies are needed to confirm this concept. It is not yet clear whether hepcidin exerts any iron-independent effects on host defenses

Mechanisms of hepcidin induction.

<p>In hepatocytes, hepcidin induction is mediated primarily by BMP ligands binding with the HJV/BMPR complex. BMP6 is induced by high iron levels via an undefined mechanism. The protease TMPRSS6 inhibits hepcidin production by degrading HJV in response to low iron levels [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004998#ppat.1004998.ref095" target="_blank">95</a>]. High holo-transferrin levels stabilize the transferrin receptor 2 (Tfr2)/HFE complex, which promotes hepcidin induction, possibly by direct binding with HJV or BMPR [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004998#ppat.1004998.ref100" target="_blank">100</a>]. Hepcidin can also be induced by IL-6 via STAT3 signaling in hepatocytes and myeloid leukocytes. Inflammation can stimulate hepcidin production in myeloid leukocytes through pathogen recognition receptor signaling and through autocrine and paracrine production of IL-6.</p

The effect of hepcidin on iron homeostasis.

<p>In the absence of hepcidin, iron absorbed from the diet by duodenal enterocytes is transported into the serum via ferroportin, and iron captured from senescent red blood cells is exported from splenic macrophages. In the presence of hepcidin, iron is retained in duodenal enterocytes, which eventually shed from the intestinal tract, blocking iron absorption from the diet. Mononuclear phagocytes retain and accumulate recycled iron rather than releasing it back into circulation, causing a drop in serum iron levels.</p

A computational model of invasive aspergillosis in the lung and the role of iron.

BACKGROUND: Invasive aspergillosis is a severe infection of immunocompromised hosts, caused by the inhalation of the spores of the ubiquitous environmental molds of the Aspergillus genus. The innate immune response in this infection entails a series of complex and inter-related interactions between multiple recruited and resident cell populations with each other and with the fungal cell; in particular, iron is critical for fungal growth. RESULTS: A computational model of invasive aspergillosis is presented here; the model can be used as a rational hypothesis-generating tool to investigate host responses to this infection. Using a combination of laboratory data and published literature, an in silico model of a section of lung tissue was generated that includes an alveolar duct, adjacent capillaries, and surrounding lung parenchyma. The three-dimensional agent-based model integrates temporal events in fungal cells, epithelial cells, monocytes, and neutrophils after inhalation of spores with cellular dynamics at the tissue level, comprising part of the innate immune response. Iron levels in the blood and tissue play a key role in the fungus\u27 ability to grow, and the model includes iron recruitment and consumption by the different types of cells included. Parameter sensitivity analysis suggests the model is robust with respect to unvalidated parameters, and thus is a viable tool for an in silico investigation of invasive aspergillosis. CONCLUSIONS: Using laboratory data from a mouse model of invasive aspergillosis in the context of transient neutropenia as validation, the model predicted qualitatively similar time course changes in fungal burden, monocyte and neutrophil populations, and tissue iron levels. This model lays the groundwork for a multi-scale dynamic mathematical model of the immune response to Aspergillus species. BMC Syst Biol 2016 Apr 21; 10(1):3

Overview of host iron homeostasis.

<p>Iron is absorbed from the diet by duodenal enterocytes and transported into the bloodstream, where it is bound by transferrin. Most iron is incorporated into erythrocytes for heme synthesis. Splenic macrophages recover iron from senescent erythrocytes and release iron into circulation via ferroportin. Smaller amounts of iron are imported into other tissues as needed. Iron loss is not directly regulated and occurs through minor bleeding and shedding of duodenal enterocytes. Approximate iron content of adult human tissues is represented in parentheses.</p

Summary of the role of hepcidin in specific infections.

<p>Hepcidin-mediated iron restriction is protective against some extracellular infections and potentially detrimental in host defense against pathogens that reside in the intracellular compartment. Hepcidin has complex effects in infection by <i>Plasmodium</i> species and HCV.</p