Iron and neoplasia

Normal and neoplastic cells (like nonpathogenic and pathogenic microorganisms) apparently have similar needs and tolerances for iron, but neoplastic cells (like pathogenic microorganisms) may exhibit altered mechanisms of iron acquisition that permit continued growth in host iron-restricted tissues. Excess iron tends to interfere with host defense against malignant cells (as well as against microbial invaders); severe iron deficiency may likewise be detrimental. Elevated temperature is more toxic towards neoplastic than to normal host cells; it is not yet known whether the site of action of heat might be associated with iron acquisition (as has been demonstrated for gram negative bacteria). Persons or animals with iron overload tend to be at greater risk than normal hosts in the development of neoplasms. Construction of animal models of iron overload, although difficult, is strongly indicated at this time. Based on such models, decisions then can be made about the extent to which (a) nutritional immunity against neoplastic cells is practiced by vertebrate hosts and (b) clinical procedures could be employed to strengthen such immunity as an adjunct to radiotherapy, chemotherapy, and surgery.     

Apoptotic cell death of macrophages by iron-stressed <Emphasis Type="Italic">Salmonella enterica </Emphasis>serovar Typhimurium

Salmonella spp. have been shown to cause apoptosis of various host cell types as a part of their infection process. However, the induction of apoptosis remains to be looked into under the different host environments experienced by the pathogens. One of these is iron limitation, due to binding of iron in the host with proteins like lactoferrin, transferrin, haptoglobulin and hemoglobin etc. making non-availability of free iron to the pathogen for its growth and metabolism. In order to simulate the iron-limited in vivo situation, we studied the potential of Salmonella enterica serovar Typhimurium and its proteins under in vitro-created iron-stressed conditions, to cause apoptosis of macrophages (the first line of defence system). The apoptotic potential was evaluated qualitatively and quantitatively by various methods like assessment of nucleosomal DNA ladder (hallmark of apoptosis) and morphological evaluation by DNA intercalating dyes like acridine orange staining and Hoechst 33342-propidium iodide co-staining. It was observed that iron limitation could cause apoptotic cell death in a higher number of cells with the overexpression of proteins with subunit molecular weights of approximately 89, 54, 32 and 20 kDa. Salmonella may initiate apoptosis as a virulence strategy, but the death of host cells by the process of apoptosis rather than necrosis after getting a suicidal signal might be helpful for the host in order to save the surrounding cells, as well as to the parasite to enable it to spread systemically without inducing an inflammatory response.     

Iron withholding: A defense against viral infections

A variety of laboratory and clinical investigations during the past 15 years have observed that one of the dangers of excessive iron is its ability to favor animal viral infections. The metal is essential for host cell synthesis of virions and can also impair defense cell function and increase oxidative stress. In both animal models and humans, viral infections cause upregulation of the iron withholding defense system. Factors that suppress the system enhance viral progression; factors that strengthen the system augment host defense. Procedures designed to reinforce the system are being developed and tested; some of these may become useful adjuncts in prevention and management of viral diseases.     

Hypothesis: Iron chelation plays a vital role in neutrophilic inflammation

Neutrophil influx into tissues occurs in many diverse diseases and can be associated with both beneficial and injurious effects. We hypothesize that the stimulus for certain neutrophilic inflammatory responses can be reduced to a series of competing reactions for iron, with either a labile or reactive coordination site available, between host chelators and chelators not indigenous to that specific living system. The iron focuses the transport of host phagocytic cells through a metal catalyzed generation of oxidant sensitive mediators including cytokines and eicosanoids. Many of these products are chemotactic for neutrophils. We also postulate that the iron increases the activity of the phagocyte associated NADPH oxidoreductase in the neutrophil. The function of this enzyme is likely to be the generation of superoxide in the hostÕs attempt to chemically reduce and dislodge the iron from its chelate complex. After the reoxidation of Fe in an aerobic environment, Fe will be coordinated by host lactoferrin released by the neutrophil. When complexed by this glycoprotein, the metal does not readily undergo oxidation/reduction and is safely transported to the macrophages of the reticuloendothelial system where it is stored in ferritin. Finally, we propose that the neutrophil will attempt to destroy the chelator not indigenous to the host by releasing granular contents other than lactoferrin. Inability to eliminate the chelator allows this sequence to repeat itself, which can lead to tissue injury. Such persistence of a metal chelate in the host may be associated with biomineralization, fibrosis, and cancer.     

Roles of iron in neoplasia

Research and clinical observations during the past six decades have shown that: 1. Iron promotes cancer cell growth; 2. Hosts attempt to withhold or withdraw iron from cancer cells; and 3. Iron is a factor in prevention and in therapy of neoplastic disease. Although normal and neoplastic cells have similar qualitative requirements for iron, the neoplastic cells have more flexibility in acquisition of the metal. Excessive iron levels in animals and humans are associated with enhanced neoplastic cell growth. In invaded hosts, cytokine-activated macrophages increase intracellular ferritin retention of the metal, scavenge iron in areas of tumor growth, and secrete reactive nitrogen intermediates to effect efflux of nonheme iron from tumor cells. Procedures associated with lowering host intake of excess iron can assist in prevention and in management of neoplastic disease. Chemical methods for prevention of iron assimilation by neoplastic cells are being developed in experimental and clinical protocols. The antineoplastic activity of a considerable variety of chemicals, as well as of radiation, is modulated by iron. The present article focuses on recent findings and suggests directions for further cancer-iron research.     

Candida albicans iron acquisition within the host

As a commensal and opportunistic pathogen, Candida albicans possesses a range of determinants that contribute to survival, persistence and virulence. Among this repertoire of fitness and virulence attributes are iron acquisition factors and pathways, which allow fungal cells to gain this essential mineral in the iron-poor environment of the host. The aim of this review is to present the strategies used by C. albicans to exploit host iron reservoirs and their impact on C. albicans pathogenicity. Because iron in the human host is mostly linked to host proteins, pathogens such as C. albicans must possess mechanisms to gain iron from these proteins. Here, we introduce the most important groups of human proteins, including haemoglobin, transferrin, lactoferrin and ferritin, which contain iron and that are potential iron sources for invading microorganisms. We then summarize and discuss the known and proposed strategies by which C. albicans exploits or may exploit iron from host proteins and compare these with strategies from other pathogenic microorganisms.     

Characterization of a nucleus located mollusc mitoferrin and its response to OsHV-1 infection

Mitoferrin genes as members of SLC25 family are conservatively existed across species, mainly locate on mitochondria and serve an important role in the regulation of whole cellular iron metabolism. Available iron withholding from pathogens presents an important host defense strategy, while the regulation role of mitoferrin against invading pathogens is largely unknown. In this study, a unique mollusc mitoferrin gene was identified in ark clams, named SbmiFn, that showed conserved three-dimensional structure with other mitoferrins, and its iron binding activity was verified by iron chelating assay. Besides cytoplasmic distribution, colocalization between SbmiFn and nuclei was observed by immunohistochemistry assay. Moreover, the response of SbmiFn to viral pathogen OsHV-1 was investigated. The results showed that nucleus located signal of SbmiFn was enhanced, the expressions of SbmiFn and ferritin were coordinately decreased, which might assist host against OsHV-1 replication as the increase of OsHV-1 copies were hardly detected after that. These results refreshed our knowledge on the sequence, structure and functional characteristics of mitoferrin subfamily, and would contribute to further comparative studies on iron metabolism.     

Potential lactoferrin activity against pathogenic viruses

Lactoferrin (LF) is an 80-kDa globular glycoprotein with high affinity for metal ions, particularly for iron. This protein possesses many biological functions, including the binding and release of iron and serves as one of the important components of the innate immune system, where it acts as a potent inhibitor of several pathogens. LF has efficacious antibacterial and antiviral activities against a wide range of Gram-positive and Gram-negative bacteria and against both naked and enveloped DNA and RNA viruses. In its antiviral pursuit, LF acts predominantly at the acute phase of the viral infection or even at the intracellular stage, as in hepatitis C virus infection. LF inhibits the entry of viral particles into host cells, either by direct attachment to the viral particles or by blocking their cellular receptors. This wide range of activities may be attributed to the capacity of LF to bind iron and its ability to interfere with the cellular receptors of both hosts and pathogenic microbes.     

Siderophore-Mediated Utilization of Iron Bound to Transferrin by Vibrio parahaemolyticus

Vibrio parahaemolyticus produces a structurally novel type of siderophore, termed vibrioferrin, in response to iron-limitation. This study was performed to examine whether vibrioferrin can assimilate iron from human iron-binding proteins for growth. Comparison of the growth rates between V. parahaemolyticus AQ 3354 and its spontaneously arising, vibrioferrin-deficient mutant revealed that vibrioferrin was able to sequester iron from 30% iron-saturated human transferrin for growth, but not from human lactoferrin even if fully saturated with iron. In both strains, iron limitation induced two high-molecular-weight outer membrane proteins with apparent molecular masses of approximately 78 and 83 kDa. Since only the outer membrane fraction including these proteins showed a binding capacity to ferric vibrioferrin complex, either of them may function as its cell surface receptor. These results suggested that the organism might utilize such a source of host iron through the action of vibrioferrin during in vivo survival and proliferation, although its importance in pathogenesis is unknown.     

Structural basis for hemoglobin capture by Staphylococcus aureus cell-surface protein, IsdH

Pathogens must steal iron from their hosts to establish infection. In mammals, hemoglobin (Hb) represents the largest reservoir of iron, and pathogens express Hb-binding proteins to access this source. Here, we show how one of the commonest and most significant human pathogens, Staphylococcus aureus, captures Hb as the first step of an iron-scavenging pathway. The x-ray crystal structure of Hb bound to a domain from the Isd (iron-regulated surface determinant) protein, IsdH, is the first structure of a Hb capture complex to be determined. Surface mutations in Hb that reduce binding to the Hb-receptor limit the capacity of S. aureus to utilize Hb as an iron source, suggesting that Hb sequence is a factor in host susceptibility to infection. The demonstration that pathogens make highly specific recognition complexes with Hb raises the possibility of developing inhibitors of Hb binding as antibacterial agents.     

The crystal structure of Klebsiella pneumoniae FeoA reveals a site for protein-protein interactions

In order to establish infection, pathogenic bacteria must obtain essential nutrients such as iron. Under acidic and/or anaerobic conditions, most bacteria utilize the Feo system in order to acquire ferrous iron (Fe²⁺) from their host environment. The mechanism of this process, including its regulation, remains poorly understood. In this work, we have determined the crystal structure of FeoA from the nosocomial agent Klebsiella pneumoniae (KpFeoA). Our structure reveals an SH3-like domain that mediates interactions between neighboring polypeptides via hydrophobic intercalations into a Leu-rich surface ridge. Using docking of a small peptide corresponding to a postulated FeoB partner binding site, we demonstrate that KpFeoA can assume both “open” and “closed” conformations, controlled by binding at this Leu-rich ridge. We propose a model in which a “C-shaped” clamp along the FeoA surface mediates interactions with its partner protein, FeoB. These findings are the first to demonstrate atomic-level details of FeoA-based protein-protein interactions and provide a framework for testing FeoA-FeoB interactions, which could be exploited for future antibiotic developments.     

Haemophore functions revisited

Haem is the major iron source for bacteria that develop in higher organisms. In these hosts, bacteria have to cope with nutritional immunity imposed by the host, since haem and iron are tightly bound to carrier and storage proteins. Siderophores were the first recognized fighters in the battle for iron between bacteria and host. They are non-proteinaceus organic molecules having an extremely high affinity for Fe(3+) and able to extract it from host proteins. Haemophores, that display functional analogy with siderophores, were more recently discovered. They are a class of secreted proteins with a high affinity for haem; they are able to extract haem from host haemoproteins and deliver it to specific receptors that internalize haem. In the past few years, a wealth of data has accumulated on haem acquisition systems that are dependent on surface exposed/secreted bacterial proteins. They promote haem transfer from its initial source (in most cases, a eukaryotic haem binding protein) to the transporter that carries out the membrane crossing step. Here we review recent discoveries in this field, with particular emphasis on similar and dissimilar mechanisms in haemophores and siderophores, from the initial host source to the binding protein/receptor at the cell surface.     

Iron and siderophores in fungal–host interactions

Most fungi and bacteria express specific mechanisms for the acquisition of iron from the hosts they infect for their own survival. This is primarily because iron plays a key catalytic role in various vital cellular reactions in conjunction with the fact that iron is not freely available in these environments due to host sequestration. High-affinity iron uptake systems, such as siderophore-mediated iron uptake and reductive iron assimilation, enable fungi to acquire limited iron from animal or plant hosts. Regulating iron uptake is crucial to maintain iron homeostasis, a state necessary to avoid iron-induced toxicity from iron abundance, while simultaneously supplying iron required for biochemical demand. Siderophores play diverse roles in fungal–host interactions, many of which have been principally delineated from gene deletions in non-ribosomal peptide synthetases, enzymes required for siderophore biosynthesis. These analyses have demonstrated that siderophores are required for virulence, resistance to oxidative stress, asexual/sexual development, iron storage, and protection against iron-induced toxicity in some fungal organisms. In this review, the strategies fungi employ to obtain iron, siderophore biosynthesis, and the regulatory mechanisms governing iron homeostasis will be discussed with an emphasis on siderophore function and relevance for fungal organisms in their interactions with their hosts.     

Modulation of intramacrophage iron metabolism during microbial cell invasion

The mechanisms whereby vertebrate hosts withhold iron from microbial invaders, as well as the methods used in attempts by invaders to capture the growth-essential metal, differ between host extracellular and intracellular environments. This review focuses on procedures employed by host cells and by invaders, respectively, that alter intramacrophage iron metabolism.     

FBXL5:一种维持细胞内铁稳态的泛素连接酶

细胞内铁稳态的维持主要通过铁调节蛋白(ironregulatory protein,IRP)与几种铁代谢基因如转铁蛋白受体和铁蛋白mRNA上铁应答元件结合来实现。铁不足可增加IRP2活性和含量,而铁过载则诱导了IRP2的泛素化和蛋白降解。F-盒蛋白FBXL5是一种铁和氧依赖的E3泛素连接酶,在铁和氧存在的情况下催化IRP2的泛素化,而缺铁或缺氧则造成FBXL5自身被泛素化修饰和随后的蛋白酶体降解。FBXL5铁调节功能的发现使人们对细胞内铁稳态的理解更为清晰。     

Specialist by preference,generalist by need: availability of quality hosts drives parasite choice in a natural multihost–parasite system

Encountering suitable hosts is key for parasite success. A general assumption for disease transmission is that the contact of a parasite with a potential host is driven by the density or relative frequency of hosts. That assumption ignores the potential role of differential host attractiveness for parasites that can drive the encounter of hosts. It has been posited that hosts may be chosen by parasites as a function of their suitability, but the existing literature addressing that hypothesis is still very scarce. In a natural system involving a parasitic Philornis botfly and its multiple bird hosts, there are profound differences in host quality. The Great Kiskadee tolerates and does not invest in resisting the infection, which makes it an optimal host. Alternative hosts are frequently used, but whilst some of them may be good options, others are bad alternatives. Here we examined the host selection processes that drive parasite dynamics in this system with 8 years of data from a longitudinal study under natural conditions. We found that the use of an alternative host was not driven by its density or relative frequency, but instead selection of these hosts was strongly dependent on availability of more suitable hosts. When optimal hosts are plentiful, the parasite tends to ignore alternative ones. As broods of optimal hosts become limited, good alternative hosts are targeted. The parasite chooses bad alternative hosts only when better alternatives are not sufficiently available. These results add evidence from a natural system that some parasites choose their hosts as a function of their profitability, and show that host selection by this parasite is plastic and context-dependent. Such findings could have important implications for the epidemiology of some parasitic and vector-borne infections which should be considered when modelling and managing those diseases. The facultative host selection observed here can be of high relevance for public health, animal husbandry, and biodiversity conservation, because reductions in the richness of hosts might cause humans, domestic animals, or endangered species to become increasingly targeted by parasites that can drive the encounter of hosts.     

Lactoferrin: Role in iron homeostasis and host defense against microbial infection

The transferrin family of non-heme iron binding glycoproteins are believed to play a central role in iron metabolism and have been implicated in iron transport, cellular iron delivery and control of the level of free iron in external secretions. Lactoferrin (LF) is a member of this family that is widely localized in external fluids including milk and mucosal secretions, in addition to being a prominent component of the secondary granules of neutrophils. Although structurally related to transferrin, LF appears to have a broader functional role mediated by both iron dependent and iron independent mechanisms. In this review, we will focus on our current understanding on the role of LF in regulating iron homeostasis and its role in host protection against microbial infection at the mucosal surface. In addition, recent insights obtained from analyzing the phenotypic consequences of LF ablation in lactoferrin knockout mice (LFKO), which challenge the long held dogma that LF is required for intestinal iron absorption in the neonate, are summarized.     

The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity

Although iron is required for cell proliferation, iron‐dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron‐mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of iron‐responsive element‐binding protein 2 (IREB2), selectively reduced in colorectal cancer. Clinically, downregulation of OTUD1 is highly correlated with poor outcome of cancer. Mechanistically, OTUD1 promotes transferrin receptor protein 1 (TFRC)‐mediated iron transportation through deubiquitinating and stabilizing IREB2, leading to increased ROS generation and ferroptosis. Moreover, the presence of OTUD1 promotes the release of damage‐associated molecular patterns (DAMPs), which in turn recruits the leukocytes and strengthens host immune response. Reciprocally, depletion of OTUD1 limits tumor‐reactive T‐cell accumulation and exacerbates colon cancer progression. Our data demonstrate that OTUD1 plays a stimulatory role in iron transportation and highlight the importance of OTUD1‐IREB2‐TFRC signaling axis in host antitumor immunity.     

Iron metabolism: microbes,mouse, and man

Recent advances in research on iron metabolism have revealed the identity of a number of genes, signal transduction pathways, and proteins involved in iron regulation in mammals. The emerging paradigm is a coordination of homeostasis within a network of classical iron metabolic pathways and other cellular processes such as cell differentiation, growth, inflammation, immunity, and a host of physiologic and pathologic conditions. Iron, immunity, and infection are intricately linked and their regulation is fundamental to the survival of mammals. The mutual dependence on iron by the host and invading pathogenic organisms elicits competition for the element during infection. While the host maintains mechanisms to utilize iron for its own metabolism exclusively, pathogenic organisms are armed with a myriad of strategies to circumvent these measures. This review explores iron metabolism in mammalian host, defense mechanisms against pathogenic microbes and the competitive devices of microbes for access to iron.     

革兰氏阴性菌亚铁离子转运系统的组成及作用机制

几乎所有细菌的生长都离不开铁元素。在有氧的环境中,三价铁离子几乎无法被细菌直接利用。但是在宿主胃肠道中,铁元素主要以可溶性的亚铁离子形式存在,它们可通过革兰氏阴性菌外膜直接进入胞周质,在周质通过亚铁离子转运系统,将铁离子转运至胞浆供细菌利用。绝大多数阴性菌主要是通过Feo转运系统利用亚铁离子,大肠杆菌的Feo转运系统由feoA、feoB和feoC3个基因组成。除Feo转运系统外,还发现Yfe转运系统、Efe转运系统、Sit转运系统等。本文重点介绍革兰氏阴性菌Feo转运系统的组成及作用机制,以期为进一步研究细菌亚铁离子的转运机制提供参考。