ABSTRACT
Iron plays a critical role in immune responses. However, its role in T helper cell differentiation and function remains poorly understood. In this study, it is shown that the restraint of iron availability through blocking CD71-mediated iron endocytosis impaired the differentiation and pathogenicity of TH 17 cells. Administrations of anti-CD71 mAb could relieve the development of experimental autoimmune encephalomyelitis (EAE). Mechanistically, the iron deficiency due to the blocking of CD71 enhanced IL-2 expression, which further restrained the differentiation of TH 17 cells. Meanwhile, CD71 blockade impaired histone modifications of Il17 gene and reduced the recruitment of RORγt to Il17a locus. In sum, the findings reveal that iron plays a pivotal role in regulating TH 17 cell differentiation and function in autoimmune diseases.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/immunology , Iron/immunology , Iron/metabolism , Th17 Cells/immunology , Animals , Antigens, CD/immunology , Antigens, CD/metabolism , Cell Differentiation/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Mice , Mice, Inbred C57BL , Receptors, Transferrin/immunology , Receptors, Transferrin/metabolism , Th17 Cells/metabolismABSTRACT
It has recently emerged that tissue-resident macrophages are key regulators of several stem cell niches orchestrating tissue formation during development, as well as postnatally, when they also organize the repair and regeneration of many tissues including the hemopoietic tissue. The fact that macrophages are also master regulators and effectors of innate immunity and inflammation allows them to coordinate hematopoietic response to infections, injuries, and inflammation. After recently reviewing the roles of phagocytes and macrophages in regulating normal and pathologic hematopoietic stem cell niches, we now focus on the key roles of macrophages in regulating erythropoiesis and iron homeostasis. We review herein the recent advances in understanding how macrophages at the center of erythroblastic islands form an erythropoietic niche that controls the terminal differentiation and maturation of erythroblasts into reticulocytes; how red pulp macrophages in the spleen control iron recycling and homeostasis; how these macrophages coordinate emergency erythropoiesis in response to blood loss, infections, and inflammation; and how persistent infections or inflammation can lead to anemia of inflammation via macrophages. Finally, we discuss the technical challenges associated with the molecular characterization of erythroid island macrophages and red pulp macrophages.
Subject(s)
Erythropoiesis , Inflammation/immunology , Iron/immunology , Macrophages/immunology , Persistent Infection/immunology , Anemia/immunology , Animals , Erythroblasts/immunology , Humans , Stem Cell NicheABSTRACT
Throughout life, macrophages are located in every tissue of the body, where their main roles are to phagocytose cellular debris and recycle aging red blood cells. In the tissue niche, they promote homeostasis through trophic, regulatory, and repair functions by responding to internal and external stimuli. This in turn polarizes macrophages into a broad spectrum of functional activation states, also reflected in their iron-regulated gene profile. The fast adaptation to the environment in which they are located helps to maintain tissue homeostasis under physiological conditions.
Subject(s)
Iron/immunology , Macrophage Activation , Macrophages/immunology , Animals , Homeostasis , Humans , Inflammation/immunology , Inflammation/metabolism , Iron/metabolism , Macrophages/metabolism , PhagocytosisABSTRACT
Iron is an essential nutrient for mammals as well as for pathogens. Inflammation-driven changes in systemic and cellular iron homeostasis are central for host-mediated antimicrobial strategies. Here, we studied the role of the iron storage protein ferritin H (FTH) for the control of infections with the intracellular pathogen Salmonella enterica serovar Typhimurium by macrophages. Mice lacking FTH in the myeloid lineage (LysM-Cre+/+Fthfl/fl mice) displayed impaired iron storage capacities in the tissue leukocyte compartment, increased levels of labile iron in macrophages, and an accelerated macrophage-mediated iron turnover. While under steady-state conditions, LysM-Cre+/+Fth+/+ and LysM-Cre+/+Fthfl/fl animals showed comparable susceptibility to Salmonella infection, i.v. iron supplementation drastically shortened survival of LysM-Cre+/+Fthfl/fl mice. Mechanistically, these animals displayed increased bacterial burden, which contributed to uncontrolled triggering of NF-κB and inflammasome signaling and development of cytokine storm and death. Importantly, pharmacologic inhibition of the inflammasome and IL-1ß pathways reduced cytokine levels and mortality and partly restored infection control in iron-treated ferritin-deficient mice. These findings uncover incompletely characterized roles of ferritin and cellular iron turnover in myeloid cells in controlling bacterial spread and for modulating NF-κB and inflammasome-mediated cytokine activation, which may be of vital importance in iron-overloaded individuals suffering from severe infections and sepsis.
Subject(s)
Apoferritins , Disease Susceptibility/metabolism , Inflammation , Iron , Macrophages , Salmonella Infections , Salmonella typhimurium/immunology , Animals , Apoferritins/deficiency , Apoferritins/metabolism , Immunity, Innate , Inflammasomes/metabolism , Inflammation/metabolism , Inflammation/microbiology , Interleukin-1beta/immunology , Iron/immunology , Iron/metabolism , Macrophages/immunology , Macrophages/metabolism , Macrophages/microbiology , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Salmonella Infections/immunology , Salmonella Infections/metabolism , Signal Transduction/immunologyABSTRACT
Celiac disease (CD) and autoimmune thyroid diseases (AITD) like Hashimoto's thyroiditis (HT) and Graves' disease (GD) frequently coexist, entailing numerous potential impacts on diagnostic and therapeutic approaches. Possible correlations might exist through gut microbiota, regulating the immune system and inflammatory responses, promoting autoimmune diseases, as well as shared cytokines in pathogenesis pathways, cross-reacting antibodies or malabsorption of micronutrients that are essential for the thyroid like iron or vitamin D. Vitamin D deficiency is a common finding in patients with AITD, but might protect from autoimmunity by wielding immunoregulatory and tolerogenic impacts. Additionally, vitamin D is assumed to be involved in the onset and progression of CD, presumably plays a substantial protective role for intestinal mucosa and affects the thyroid via its immunomodulatory effects. Iron is an essential micronutrient for the thyroid gland needed for effective iodine utilization by the iron-dependent enzyme thyroid iodine peroxidase (TPO). Despite being crucial for thyroid hormone synthesis, iron deficiency (ID) is a common finding in patients with hypothyroidism like HT and is frequently found in patients with CD. A literature research was conducted to examine the interplay between CD, AITD, vitamin D and iron deficiency. This narrative review highlights the relevant correlation of the two disease entities CD and AITD, their reciprocal impact and possible therapeutic options that should be further explored by future studies.
Subject(s)
Celiac Disease/immunology , Iron/immunology , Thyroid Gland/immunology , Thyroiditis, Autoimmune/immunology , Vitamin D/immunology , Autoimmunity/immunology , Celiac Disease/blood , Gastrointestinal Microbiome/immunology , Humans , Iron/blood , Iron Deficiencies , Thyroiditis, Autoimmune/blood , Vitamin D/blood , Vitamin D Deficiency/blood , Vitamin D Deficiency/immunologyABSTRACT
BACKGROUND: Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to coronavirus disease 2019 (COVID-19) infection, progression to symptoms, likelihood of severe disease, and survival. OBJECTIVE: The aim was to review the latest evidence on how malnutrition across all its forms (under- and overnutrition and micronutrient status) may influence both susceptibility to, and progression of, COVID-19. METHODS: We synthesized information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity, and diabetes; protein-energy malnutrition; anemia; vitamins A, C, D, and E; PUFAs; iron; selenium; zinc; antioxidants; and nutritional support. For each section we provide: 1) a landscape review of pertinent material; 2) a systematic search of the literature in PubMed and EMBASE databases, including a wide range of preprint servers; and 3) a screen of 6 clinical trial registries. All original research was considered, without restriction to study design, and included if it covered: 1) severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV), or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16 May and 11 August 2020. RESULTS: Across the 13 searches, 2732 articles from PubMed and EMBASE, 4164 articles from the preprint servers, and 433 trials were returned. In the final narrative synthesis, we include 22 published articles, 38 preprint articles, and 79 trials. CONCLUSIONS: Currently there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery. However, results of clinical trials are eagerly awaited. Given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. Furthermore, there is strong evidence that prevention of obesity and type 2 diabetes will reduce the risk of serious COVID-19 outcomes. This review is registered at PROSPERO as CRD42020186194.
Subject(s)
Anemia/epidemiology , COVID-19/epidemiology , COVID-19/immunology , Diabetes Mellitus/epidemiology , Nutritional Status , Obesity/epidemiology , Protein-Energy Malnutrition/epidemiology , Antioxidants/metabolism , COVID-19/prevention & control , COVID-19/therapy , Comorbidity , Dietary Supplements , Disease Progression , Fatty Acids, Omega-3/immunology , Fatty Acids, Omega-6/immunology , Humans , Iron/immunology , Nutritional Support , SARS-CoV-2 , Selenium/immunology , Severity of Illness Index , Vitamins/immunology , Zinc/immunologyABSTRACT
Iron deficiency, with or without anemia, is the most frequent hematological manifestation in individuals with cancer, and is especially common in patients with colorectal cancer. Iron is a vital micronutrient that plays an essential role in many biological functions, in the context of which it has been found to be intimately linked to cancer biology. To date, however, whereas a large number of studies have comprehensively investigated and reviewed the effects of excess iron on cancer initiation and progression, potential interrelations of iron deficiency with cancer have been largely neglected and are not well-defined. Emerging evidence indicates that reduced iron intake and low systemic iron levels are associated with the pathogenesis of colorectal cancer, suggesting that optimal iron intake must be carefully balanced to avoid both iron deficiency and iron excess. Since iron is vital in the maintenance of immunological functions, insufficient iron availability may enhance oncogenicity by impairing immunosurveillance for neoplastic changes and potentially altering the tumor immune microenvironment. Data from clinical studies support these concepts, showing that iron deficiency is associated with inferior outcomes and reduced response to therapy in patients with colorectal cancer. Here, we elucidate cancer-related effects of iron deficiency, examine preclinical and clinical evidence of its role in tumorigenesis, cancer progression and treatment response. and highlight the importance of adequate iron supplementation to limit these outcomes.
Subject(s)
Anemia, Iron-Deficiency/metabolism , Cell Transformation, Neoplastic/metabolism , Colorectal Neoplasms/metabolism , Iron/metabolism , Anemia, Iron-Deficiency/drug therapy , Anemia, Iron-Deficiency/immunology , Animals , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/immunology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/prevention & control , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Humans , Iron/immunology , Iron Compounds/therapeutic use , Oxidative Stress , Tumor Escape , Tumor MicroenvironmentABSTRACT
Piglets, especially weaning piglets, show a lower level of immunity and higher morbidity and mortality, owing to their rapid growth, physiological immaturity, and gradual reduction of maternal antibodies, which seriously affects their growth and thus, value. It is important that piglets adapt to nutrient digestion and absorption and develop sound intestinal function and colonization with gut microbiota as soon as possible during their early life stage. Lactoferrin is a natural glycoprotein polypeptide that is part of the transferrin family. It is widely found in mucosal secretions such as saliva and tears, and most highly in milk and colostrum. As a multifunctional bioactive protein and a recommended food additive, lactoferrin is a potential alternative therapy to antibiotics and health promoting additive for piglet nutrition and development. It is expected that lactoferrin, as a natural food additive, could play an important role in maintaining pig health and development. This review examines the following known beneficial effects of lactoferrin: improves the digestion and capacity for absorption in the intestinal tract; promotes the absorption of iron and reduces the incidence of iron deficiency anemia; regulates intestinal function and helps to balance the microbial biota; and enhances the resistance to disease of the piglets via modulating and enhancing the immune system.
Subject(s)
Lactoferrin/immunology , Animals , Animals, Newborn , Gastrointestinal Microbiome , Intestines , Iron/immunology , SwineABSTRACT
Haemophilic arthropathy (HA), caused by intra-articular haemorrhage, is one of the most common complications in patients with haemophilia. Factor replacement therapy provides missing coagulation factors to prevent children with haemophilia from joint bleeding and decreases their risk for HA. However, haemophilia patients in developing countries are still suffering from HA due to insufficient replacement therapy. Symptoms such as pain and activity limitations caused by HA seriously affect the functional abilities and quality of life of patients with HA, causing a high disability rate in the haemophilia cohort. The pathological mechanism of HA is complicated because the whole pathological mainly involves hypertrophic synovitis, osteopenia, cartilage and bone destruction, and these pathological changes occur in parallel and interact with each other. Inflammation plays an important role in the whole complex pathological process, and iron, cytokines, growth factors and other factors are involved. This review summarizes the pathological mechanism of HA to provide background for clinical and basic research.
Subject(s)
Arthritis/pathology , Bone Diseases, Metabolic/pathology , Hemarthrosis/pathology , Hemophilia A/pathology , Osteonecrosis/pathology , Synovitis/pathology , Adult , Arthritis/genetics , Arthritis/immunology , Arthritis/metabolism , Bone Diseases, Metabolic/genetics , Bone Diseases, Metabolic/immunology , Bone Diseases, Metabolic/metabolism , Child , Cytokines/genetics , Cytokines/immunology , Factor VIII/therapeutic use , Gene Expression Regulation , Hemarthrosis/genetics , Hemarthrosis/immunology , Hemarthrosis/metabolism , Hemophilia A/genetics , Hemophilia A/immunology , Hemophilia A/metabolism , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/immunology , Iron/immunology , Iron/metabolism , Joints/immunology , Joints/metabolism , Joints/pathology , Osteonecrosis/genetics , Osteonecrosis/immunology , Osteonecrosis/metabolism , Quality of Life , Synovitis/genetics , Synovitis/immunology , Synovitis/metabolismSubject(s)
Hypersensitivity , Animals , Asthma/drug therapy , Asthma/immunology , Cosmetics/adverse effects , Humans , Hypersensitivity/complications , Hypersensitivity/immunology , Hypersensitivity/prevention & control , Hypersensitivity/therapy , Interleukin-33/antagonists & inhibitors , Interleukin-33/immunology , Iron/chemistry , Iron/immunology , Lactoglobulins/chemistry , Lactoglobulins/immunology , Mice , Milk Hypersensitivity/immunology , Peanut Hypersensitivity/immunology , Peanut Hypersensitivity/prevention & control , Peanut Hypersensitivity/therapy , Pruritus/chemically induced , Pruritus/complications , Pruritus/immunology , Pruritus/prevention & control , Pyroglyphidae/immunology , Serum Amyloid A Protein/deficiency , Serum Amyloid A Protein/immunology , Skin/immunology , Skin/pathology , T-Lymphocytes/immunology , TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/immunologyABSTRACT
Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.
Subject(s)
Ferroptosis , Glioblastoma/physiopathology , Neutrophils/immunology , Animals , Cell Line, Tumor , Coenzyme A Ligases/genetics , Coenzyme A Ligases/immunology , Disease Progression , Female , Glioblastoma/genetics , Glioblastoma/immunology , Glioblastoma/pathology , Humans , Iron/immunology , Mice , Mice, Nude , Necrosis , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/immunologyABSTRACT
Chronic inflammation mediated by nuclear factor-κB (NF-κB) plays a crucial role in the development of cancer. As part of our continuous efforts placed on investigating anticancer mechanisms of dietary catechols, we further applied catechol-type diphenylbutadiene (3,4-DHB) as a model molecule to probe whether it inhibits inflammation by its pro-oxidative role. Employing lipopolysaccharide-stimulated RAW264.7 cells as a model of inflammation, we validated that benefiting from its catechol moiety, 3,4-DHB inhibited significantly the LPS-induced formation of NO (11.48 ± 0.39 µM) compared with the only LPS-stimulated group (31.8 ± 1.78 µM) with an inhibitory rate of 64% at 5 µM, expression of iNOS and COX-2 proteins, phosphorylation of IkB kinase and IkBα, and nuclear translocation of NF-κB. Noticeably, its inhibitory activity against the NF-κB-mediated inflammation can be obviously revised by pretreatment of the cells with dithiothreitol (a quencher of both electrophilic o-quinone and ROS), neocuproine (a specific chelating agent for copper ions), and deferoxamine (a specific chelating agent for iron ions). The above results support that depending on intracellular copper and iron ions, 3,4-DHB, a pro-electrophile, can be converted into its corresponding o-quinone electrophile together with the generation of ROS, a pro-oxidative event that mediates its inhibitory activity against NF-κB signaling and inflammation. The copper- and iron-dependent inhibition against inflammation supports that dietary catechols are probably pro-oxidative anti-inflammatory agents.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Butadienes/pharmacology , Catechols/administration & dosage , Copper/immunology , Inflammation/immunology , Iron/immunology , NF-kappa B/immunology , Animals , Cyclooxygenase 2/genetics , Cyclooxygenase 2/immunology , Humans , Inflammation/drug therapy , Inflammation/genetics , Macrophages/drug effects , Macrophages/immunology , Mice , NF-kappa B/genetics , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/immunology , Oxidative Stress/drug effects , RAW 264.7 Cells , Reactive Oxygen Species/immunologyABSTRACT
Iron metabolism and the plant immune system are both critical for plant vigor in natural ecosystems and for reliable agricultural productivity. Mechanistic studies of plant iron home-ostasis and plant immunity have traditionally been carried out in isolation from each other; however, our growing understanding of both processes has uncovered significant connections. For example, iron plays a critical role in the generation of reactive oxygen intermediates during immunity and has been recently implicated as a critical factor for immune-initiated cell death via ferroptosis. Moreover, plant iron stress triggers immune activation, suggesting that sensing of iron depletion is a mechanism by which plants recognize a pathogen threat. The iron deficiency response engages hormone signaling sectors that are also utilized for plant immune signaling, providing a probable explanation for iron-immunity cross-talk. Finally, interference with iron acquisition by pathogens might be a critical component of the immune response. Efforts to address the global burden of iron deficiency-related anemia have focused on classical breeding and transgenic approaches to develop crops biofortified for iron content. However, our improved mechanistic understanding of plant iron metabolism suggests that such alterations could promote or impede plant immunity, depending on the nature of the alteration and the virulence strategy of the pathogen. Effects of iron biofortification on disease resistance should be evaluated while developing plants for iron biofortification.
Subject(s)
Homeostasis/immunology , Iron/immunology , Plant Immunity/immunology , Animals , Humans , Iron/metabolismABSTRACT
Congenital hemolytic anemias (CHAs) are a heterogeneous group of rare hereditary conditions including defects of erythrocyte membrane proteins, red cell enzymes, and disorders due to defective erythropoiesis. They are characterized by variable degree of anemia, chronic extravascular hemolysis, reduced erythrocyte life span, splenomegaly, jaundice, biliary lithiasis, and iron overload. Although few data are reported on the role of the immune system in CHAs, several immune-mediated mechanisms may be involved in the pathogenesis of these rare diseases. We reported in ~60% of patients with hereditary spherocytosis (HS), the presence of naturally-occurring autoantibodies (NAbs) directed against different membrane proteins (α- and ß-spectrin, band 3, and dematin). Positive HS subjects showed a more hemolytic pattern and NAbs were more evident in aged erythrocytes. The latter is in line with the function of NAbs in the opsonization of damaged/senescent erythrocytes and their consequent removal in the spleen. Splenectomy, usually performed to reduce erythrocyte catheresis and improve Hb levels, has different efficacy in various CHAs. Median Hb increase is 3 g/dL in HS, 1.6-1.8 g/dL in pyruvate kinase deficiency (PKD), and 1 g/dL in congenital dyserythropoietic anemias (CDA) type II. Consistently with clinical severity, splenectomy is performed in 20% of HS, 45% of CDAII, and in 60% of PKD patients. Importantly, sepsis and thrombotic events have been registered, particularly in PKD with a frequency of ~7% for both. Furthermore, we analyzed the role of pro-inflammatory cytokines and found that interleukin 10 and interferon γ, and to a lesser extent interleukin 6, were increased in all CHAs compared with controls. Moreover, CDAII and enzymatic defects showed increased tumor necrosis factor-α and reduced interleukin 17. Finally, we reported that iron overload occurred in 31% of patients with membrane defects, in ~60% of CDAII cases, and in up to 82% of PKD patients (defined by MRI liver iron concentration >4 mg Fe/gdw). Hepcidin was slightly increased in CHAs compared with controls and positively correlated with ferritin and with the inflammatory cytokines interleukin 6 and interferon γ. Overall the results suggest the existence of a vicious circle between chronic hemolysis, inflammatory response, bone marrow dyserythropoiesis, and iron overload.
Subject(s)
Anemia, Hemolytic, Congenital/immunology , Animals , Antibodies/immunology , Cytokines/immunology , Erythropoietin/immunology , Humans , Immune System , Iron/immunology , Spleen/immunology , Spleen/surgery , SplenectomyABSTRACT
Transferrin receptor 1 (TfR1), encoded by the TFRC gene, is the gatekeeper of cellular iron uptake for cells. A variety of molecular mechanisms are at work to tightly regulate TfR1 expression, and abnormal TfR1 expression has been associated with various diseases. In the current study, to determine the regulation pattern of TfR1, we cloned and overexpressed the human TFRC gene in HeLa cells. RNA-sequencing (RNA-seq) was used to analyze the global transcript levels in overexpressed (OE) and normal control (NC) samples. A total of 1669 differentially expressed genes (DEGs) were identified between OE and NC. Gene ontology (GO) analysis was carried out to explore the functions of the DEGs. It was found that multiple DEGs were associated with ion transport and immunity. Moreover, the regulatory network was constructed on basis of DEGs associated with ion transport and immunity, highlighting that TFRC was the node gene of the network. These results together suggested that precisely controlled TfR1 expression might be not only essential for iron homeostasis, but also globally important for cell physiology, including ion transport and immunity.
Subject(s)
Gene Regulatory Networks/genetics , Immunity/genetics , Ion Transport/genetics , Ion Transport/immunology , Iron/immunology , Receptors, Transferrin/genetics , Receptors, Transferrin/immunology , Cell Line, Tumor , Gene Regulatory Networks/immunology , HeLa Cells , Homeostasis/genetics , Homeostasis/immunology , Humans , Immunity/immunologyABSTRACT
Staphylococcus aureus is a major human pathogen, and the emergence of antibiotic-resistant strains is making all types of S. aureus infections more challenging to treat. With a pressing need to develop alternative control strategies to use alongside or in place of conventional antibiotics, one approach is the targeting of established virulence factors. However, attempts at this have had little success to date, suggesting that we need to better understand how this pathogen causes disease if effective targets are to be identified. To address this, using a functional genomics approach, we have identified a small membrane-bound protein that we have called MspA. Inactivation of this protein results in the loss of the ability of S. aureus to secrete cytolytic toxins, protect itself from several aspects of the human innate immune system, and control its iron homeostasis. These changes appear to be mediated through a change in the stability of the bacterial membrane as a consequence of iron toxicity. These pleiotropic effects on the ability of the pathogen to interact with its host result in significant impairment in the ability of S. aureus to cause infection in both a subcutaneous and sepsis model of infection. Given the scale of the effect the inactivation of MspA causes, it represents a unique and promising target for the development of a novel therapeutic approach.
Subject(s)
Bacteremia/microbiology , Immune Evasion , Staphylococcal Infections/microbiology , Staphylococcal Skin Infections/microbiology , Staphylococcus aureus/pathogenicity , Virulence Factors/genetics , A549 Cells , Animals , Bacteremia/immunology , Bacteremia/pathology , Bacterial Toxins/genetics , Bacterial Toxins/immunology , Erythrocytes/drug effects , Gene Expression Profiling , Gene Expression Regulation , Heme/immunology , Heme/metabolism , Hemolysin Proteins/genetics , Hemolysin Proteins/immunology , Homeostasis/immunology , Humans , Iron/immunology , Iron/metabolism , Mice, Inbred BALB C , Mice, Inbred C57BL , Mutation , Phagocytosis , Proteomics/methods , Staphylococcal Infections/immunology , Staphylococcal Infections/pathology , Staphylococcal Skin Infections/immunology , Staphylococcal Skin Infections/pathology , Staphylococcal Toxoid/genetics , Staphylococcal Toxoid/immunology , Staphylococcus aureus/genetics , Staphylococcus aureus/immunology , THP-1 Cells , Virulence , Virulence Factors/immunology , Virulence Factors/toxicity , alpha-Defensins/genetics , alpha-Defensins/immunologyABSTRACT
Fungal pathogen Candida albicans has a complex cell wall consisting of an outer layer of mannans and an inner layer of ß-glucans and chitin. The fungal cell wall is the primary target for antifungals and is recognized by host immune cells. Environmental conditions such as carbon sources, pH, temperature, and oxygen tension can modulate the fungal cell wall architecture. Cellular signaling pathways, including the mitogen-activated protein kinase (MAPK) pathways, are responsible for sensing environmental cues and mediating cell wall alterations. Although iron has recently been shown to affect ß-1,3-glucan exposure on the cell wall, we report here that iron changes the composition of all major C. albicans cell wall components. Specifically, high iron decreased the levels of mannans (including phosphomannans) and chitin; and increased ß-1,3-glucan levels. These changes increased the resistance of C. albicans to cell wall-perturbing antifungals. Moreover, high iron cells exhibited adequate mitochondrial functioning; leading to a reduction in accumulation of lactate that signals through the transcription factor Crz1 to induce ß-1,3-glucan masking in C. albicans We show here that iron-induced changes in ß-1,3-glucan exposure are lactate-dependent; and high iron causes ß-1,3-glucan exposure by preventing lactate-induced, Crz1-mediated inhibition of activation of the fungal MAPK Cek1. Furthermore, despite exhibiting enhanced antifungal resistance, high iron C. albicans cells had reduced survival upon phagocytosis by macrophages. Our results underscore the role of iron as an environmental signal in multiple signaling pathways that alter cell wall architecture in C. albicans, thereby affecting its survival upon exposure to antifungals and host immune response.
Subject(s)
Antifungal Agents/pharmacology , Candida albicans , Candidiasis , Cell Wall , Iron , Lactic Acid , Macrophages , Phagocytosis , Animals , Candida albicans/immunology , Candida albicans/metabolism , Candidiasis/drug therapy , Candidiasis/immunology , Candidiasis/metabolism , Cell Wall/immunology , Cell Wall/metabolism , Female , Iron/immunology , Iron/metabolism , Lactic Acid/immunology , Lactic Acid/metabolism , Macrophages/immunology , Macrophages/microbiology , MiceABSTRACT
Serratia marcescens is a bacterium frequently found in the environment, but over the last several decades it has evolved into a concerning clinical pathogen, causing fatal bacteremia. To establish such infections, pathogens require specific nutrients; one very limited but essential nutrient is iron. We sought to characterize the iron acquisition systems in S. marcescens isolate UMH9, which was recovered from a clinical bloodstream infection. Using RNA sequencing (RNA-seq), we identified two predicted siderophore gene clusters (cbs and sch) that were regulated by iron. Mutants were constructed to delete each iron acquisition locus individually and in conjunction, generating both single and double mutants for the putative siderophore systems. Mutants lacking the sch gene cluster lost their iron-chelating ability as quantified by the chrome azurol S (CAS) assay, whereas the cbs mutant retained wild-type activity. Mass spectrometry-based analysis identified the chelating siderophore to be serratiochelin, a siderophore previously identified in Serratia plymuthica Serratiochelin-producing mutants also displayed a decreased growth rate under iron-limited conditions created by dipyridyl added to LB medium. Additionally, mutants lacking serratiochelin were significantly outcompeted during cochallenge with wild-type UMH9 in the kidneys and spleen after inoculation via the tail vein in a bacteremia mouse model. This result was further confirmed by an independent challenge, suggesting that serratiochelin is required for full S. marcescens pathogenesis in the bloodstream. Nine other clinical isolates have at least 90% protein identity to the UMH9 serratiochelin system; therefore, our results are broadly applicable to emerging clinical isolates of S. marcescens causing bacteremia.
Subject(s)
Bacteremia/microbiology , Bacterial Proteins/genetics , Iron/metabolism , Serratia Infections/microbiology , Serratia marcescens/genetics , Serratia marcescens/pathogenicity , Siderophores/genetics , Animals , Bacteremia/blood , Bacteremia/immunology , Bacteremia/pathology , Bacterial Proteins/immunology , Binding, Competitive , Female , Gene Deletion , Gene Expression Regulation , Genetic Complementation Test , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Ion Transport , Iron/immunology , Mice , Mice, Inbred CBA , Multigene Family , Protein Binding , Serratia Infections/blood , Serratia Infections/immunology , Serratia Infections/pathology , Serratia marcescens/immunology , Siderophores/immunology , VirulenceABSTRACT
Iron sequestration is a recognized innate immune mechanism against invading pathogens mediated by iron-binding proteins called transferrins. Despite many studies on antimicrobial activity of transferrins in vitro, their specific in vivo functions are poorly understood. Here we use Drosophila melanogaster as an in vivo model to investigate the role of transferrins in host defense. We find that systemic infections with a variety of pathogens trigger a hypoferremic response in flies, namely, iron withdrawal from the hemolymph and accumulation in the fat body. Notably, this hypoferremia to infection requires Drosophila nuclear factor κB (NF-κB) immune pathways, Toll and Imd, revealing that these pathways also mediate nutritional immunity in flies. Next, we show that the iron transporter Tsf1 is induced by infections downstream of the Toll and Imd pathways and is necessary for iron relocation from the hemolymph to the fat body. Consistent with elevated iron levels in the hemolymph, Tsf1 mutants exhibited increased susceptibility to Pseudomonas bacteria and Mucorales fungi, which could be rescued by chemical chelation of iron. Furthermore, using siderophore-deficient Pseudomonas aeruginosa, we discover that the siderophore pyoverdine is necessary for pathogenesis in wild-type flies, but it becomes dispensable in Tsf1 mutants due to excessive iron present in the hemolymph of these flies. As such, our study reveals that, similar to mammals, Drosophila uses iron limitation as an immune defense mechanism mediated by conserved iron-transporting proteins transferrins. Our in vivo work, together with accumulating in vitro studies, supports the immune role of insect transferrins against infections via an iron withholding strategy.
Subject(s)
Drosophila Proteins/metabolism , Iron/metabolism , Transferrin/metabolism , Animals , Drosophila Proteins/immunology , Drosophila melanogaster , Hemolymph/immunology , Hemolymph/metabolism , Immunity, Innate , Iron/immunology , NF-kappa B/metabolism , Pseudomonas aeruginosa/metabolism , Siderophores/metabolism , Transferrin/immunologyABSTRACT
Iron has long been established as a critical mediator of T cell development and proliferation. However, the mechanisms by which iron controls CD4 T cell activation and expansion remain poorly understood. In this study, we show that stimulation of CD4 T cells from C57BL/6 mice not only decreases total and labile iron levels but also leads to changes in the expression of iron homeostatic machinery. Additionally, restraining iron availability in vitro severely inhibited CD4 T cell proliferation and cell cycle progression. Although modulating cellular iron levels increased IL-2 production by activated T lymphocytes, CD25 expression and pSTAT5 levels were decreased, indicating that iron is necessary for IL-2R-mediated signaling. We also found that iron deprivation during T cell stimulation negatively impacts mitochondrial function, which can be reversed by iron supplementation. In all, we show that iron contributes to activation-induced T cell expansion by positively regulating IL-2R signaling and mitochondrial function.