Iron and parasites

In this special issue, we analyze the importance of iron in the host-parasite interplay. Iron is a transition element and the fourth most abundant element in the Earth’s crust. Iron is vital for growth of nearly all living organisms, from prokaryotes to humans. Iron plays an important role in several cellular processes, such as respiration, photosynthesis, oxygen transport, and DNA synthesis. Iron is essential but it is not easily bioavailable; ferric iron solubility is low at physiological pH whereas ferrous iron, in aerobic environments, is highly toxic. Therefore, iron is normally bound to proteins and the whole body and cellular iron concentrations have to be regulated in all organisms.

Some iron-containing and iron-binding proteins are intracellular such as the oxygen-carrier hemoglobin, the iron-storing protein ferritin, and numerous enzymes. Others are extracellular, mainly transferrin (Tf) and lactoferrin (Lf). Tf and Lf are able to capture up to two Fe3+ atoms per molecule, maintaining iron in a soluble and stable oxidation state in fluids and avoiding the generation of toxic free radicals derived from Fe2+ through the Fenton reaction. Free radicals are deleterious to most macromolecules. Tf and Lf maintain the free iron concentration too low to sustain the parasites growth. Tf is the iron transporter that allows cellular iron uptake; it is mainly found in serum and lymph. Lf is secreted into mucosae and by the secondary granules of neutrophils, to chelate the Fe3+ and avoid its availability for parasites.

Therefore, during infection, there is a constant battle between the host and the invader for iron, in which the invader attempts to have access to host iron and the host arranges complex iron-withholding mechanisms to frustrate the iron stealing. Virtually, all iron-containing proteins in eukaryotes can be used as iron sources by iron-seeking parasites; for that, several elaborate strategies have been developed by parasites to obtain host iron. Thus, capture and uptake of host iron by parasites are considered as virulence determinants.

Little information regarding iron acquisition in free-living amoebae has been reported. In the research article “Iron-Binding Protein Degradation by Cysteine Proteases of Naegleria fowleri,” M. Martínez-Castillo et al. report the cleaving of human hololactoferrin, hemoglobin, and holotransferrin by this parasite. N. fowlericauses primary amoebic meningoencephalitis. During the invasion, the microorganism interacts with different tissues such as olfactory neuroepithelium and olfactory bulbs that contain iron-binding proteins. The results show that this protozoan has several cysteine-secreted proteases that cleave iron-binding proteins. Using this strategy, N. fowleri could obtain iron from the host in the invaded tissues.

G. Ortíz-Estrada et al. address the issue about the possible way in which the human enteric parasiteEntamoeba histolytica could have access to bovine lactoferrin, a protein present in the milk mainly consumed by babies and infants fed with formula. In their research article “Binding and Endocytosis of Bovine Hololactoferrin by the Parasite Entamoeba histolytica,” the authors compare virulent trophozoites recently isolated from hamster liver abscesses with nonvirulent trophozoites maintained for more than 30 years in in vitro cultures, regarding their interaction with bovine iron-charged Lf (B-holo-Lf). Interestingly, although both amoeba variants are able to use B-holo-Lf as an iron source and endocytosed this glycoprotein through clathrin-coated vesicles, the acquisition of iron, binding parameters, and number of protein-binding sites per amoeba are different. In addition, the virulent amoebae also endocytosed B-holo-Lf through a cholesterol-dependent mechanism; thus the B-holo-Lf endocytosis is more efficient in virulent amoebae.

In the minireview article “Strategies of Intracellular Pathogens for Obtaining Iron from the Environment,” N. Leon-Sicairos et al. focus on how intracellular pathogens use multiple approaches to obtain nutritional iron from the intracellular environment, in order to use this element for replication. They explore the current knowledge about the process that occurs during infection by intracellular pathogens, where the iron is required by both the host cell and the pathogen that inhabits it. Intracellular microorganisms are destroyed by the host tissues through processes that usually involve phagocytosis and lysosomal disruption. However, some intracellular pathogens are capable of avoiding destruction by growing inside macrophages and other cells. Additionally, the implications of these mechanisms for iron acquisition in the host-pathogen relationship are discussed.

African trypanosomosis is caused by the parasitic protozoan Trypanosoma brucei. This is a chronic and debilitating disease suffered mainly by people of developing countries. In the review “Iron-Homeostasis andTrypanosoma brucei Associated Immunopathogenicity Development: A Battle/Quest for Iron,” B. Stijlemans et al. analyze the different strategies that lead to a host immune response that results in iron deprivation, consisting in an iron modulation of the host myeloid phagocytic system that affects trypanosomosis-associated anemia development.

The review article “Trichomonas vaginalis Cysteine Proteinases: Iron Response in Gene Expression and Proteolytic Activity” by R. Arroyo et al. focuses on the iron response of Trichomonas vaginalis on gene family products as the cysteine proteinases (CPs) involved in virulence properties. In particular, it examines the effect of iron in gene expression regulation and function of cathepsin L-like and asparaginyl endopeptidase-like CPs as virulence factors. Aspects regarding CPs genomic organization are addressed to offer possible explanations to the fact that only few members of this large gene family are expressed at the RNA and protein levels. Also offers possible ways used to control these particular proteolytic activities. Moreover, all known iron regulatory mechanisms of CPs at transcriptional, posttranscriptional, and posttranslational levels along with new insights into the possible epigenetic and miRNA processes in T. vaginalis are also summarized.

Finally, in the review article “Transferrin: Endocytosis and Cell Signaling in Parasitic Protozoa,” by M. Reyes-López et al., the authors describe the presence of specific receptors for Tf in protozoan parasites. The signal transduction initiated upon ligand binding at the parasite plasma membrane with the process in mammalian cells is compared, based on the large amount of information on the Tf endocytosis. Several signaling pathways participate in Tf trafficking, such as the insertion of membrane vesicles, and the signaling pathways mediated by the inositol-1,4,5-triphosphate and diacylglycerol, MAPK, or growth factors.


Limit iron intake to limit growth of invading pathogens

iron.pngIron Limitation as an Innate Immune Defense

In addition to mitigating toxicity associated with hypo- or hyperferremia, regulation of iron distribution serves as an innate immune mechanism against invading pathogens. Even in the absence of infection, several facets of human iron metabolism ensure that iron is scarcely accessible to pathogenic microorganisms. First, the majority of iron in humans is sequestered intracellularly, complexed within hemoglobin inside erythrocytes. Some pathogens have therefore evolved mechanisms to liberate hemoglobin by lysing erythrocytes to ultimately extract iron from heme. However, hemolytic pathogens must subsequently compete with haptoglobin and hemopexin, host glycoproteins that scavenge liberated hemoglobin and heme, respectively (Figure 1D). A second factor limiting the availability of iron to invading pathogens is the paucity of free extracellular iron. Extracellular iron is bound with high affinity by transferrin, which in healthy individuals is typically less than 50% saturated with iron. When transferrin-binding capacity is exceeded, iron can also be chelated with lower affinity by a number of molecules in plasma including albumin, citrate, and amino acids (Nathan et al., 2003).

During infection, additional fortification of iron-withholding defense occurs (Figure 2). The hypoferremia of infection was documented in seminal studies by Cartwright et al. in the 1940s, who noted a precipitous drop in plasma iron levels upon intramuscular inoculation of canines with Staphylococcus aureus. A similar hypoferremic response was noted upon intravenous injection with sterile turpentine, suggesting that inflammation, rather than a specific microbial product, was responsible for declining plasma iron levels (Cartwright et al., 1946). Since these initial observations, much has been learned regarding the importance of iron withholding to the outcome of host-pathogen interactions.


With the oxygenation of the Earth’s atmosphere over 2 billion years ago, abundant soluble Fe2+ was oxidized to insoluble Fe3+, making bioavailable iron much more scarce. At the same time, iron became potentially more toxic since the redox cycling of iron in the presence of oxygen and hydrogen peroxide catalyzes the production of free radicals in the Fenton reaction that can damage DNA, protein, and lipids.Humans and other organisms therefore evolved specialized proteins and tightly regulated homeostatic mechanisms for the uptake, transport, storage, and export of iron to provide adequate iron for essential biologic process, but to limit the toxicity of iron excess.

Brain iron loading impairs DNA methylation and alters GABAergic function in mice.

The term “hemochromatosis,” introduced by von Recklinghausen at the end of the 19th century, refers to the clinical disorder that results from excess of total body iron and organ failure due to iron toxicity. The disease manifestations include cirrhosis, diabetes mellitus, hypogonadism and other endocrinopathies, cardiomyopathy, arthropathy, skin pigmentation, and, in cirrhotic patients, increased susceptibility to liver cancer.

Alzheimer’s gut bacteria, virus and iron dysregulation

Researchers Identify Virus and Two Types of Bacteria as Major Causes of Alzheimer’s

A worldwide team of senior scientists and clinicians have come together to produce an editorial which indicates that certain microbes – a specific virus and two specific types of bacteria – are major causes of Alzheimer’s Disease. Their paper, which has been published online in the highly regarded peer-reviewed journal, Journal of Alzheimer’s Disease, stresses the urgent need for further research – and more importantly, for clinical trials of anti-microbial and related agents to treat the disease.

This major call for action is based on substantial published evidence into Alzheimer’s. The team’s landmark editorial summarises the abundant data implicating these microbes, but until now this work has been largely ignored or dismissed as controversial – despite the absence of evidence to the contrary. Therefore, proposals for the funding of clinical trials have been refused, despite the fact that over 400 unsuccessful clinical trials for Alzheimer’s based on other concepts were carried out over a recent 10-year period.

Opposition to the microbial concepts resembles the fierce resistance to studies some years ago which showed that viruses cause certain types of cancer, and that a bacterium causes stomach ulcers. Those concepts were ultimately proved valid, leading to successful clinical trials and the subsequent development of appropriate treatments.

Professor Douglas Kell of The University of Manchester’s School of Chemistry and Manchester Institute of Biotechnology is one of the editorial’s authors. He says that supposedly sterile red blood cells were seen to contain dormant microbes, which also has implications for blood transfusions.

“We are saying there is incontrovertible evidence that Alzheimer’s Disease has a dormant microbial component, and that this can be woken up by iron dysregulation. Removing this iron will slow down or prevent cognitive degeneration – we can’t keep ignoring all of the evidence,” Professor Douglas Kell said.

Image shows an old lady looking out of a window.

Professor Resia Pretorius of the University of Pretoria, who worked with Douglas Kell on the editorial, said “The microbial presence in blood may also play a fundamental role as causative agent of systemic inflammation, which is a characteristic of Alzheimer’s disease – particularly, the bacterial cell wall component and endotoxin, lipopolysaccharide. Furthermore, there is ample evidence that this can cause neuroinflammation and amyloid-β plaque formation.”

The findings of this editorial could also have implications for the future treatment of Parkinson’s Disease, and other progressive neurological conditions.


Source: University of Manchester
Image Credit: The image is adapted from the University of Manchester press release.
Original Research: Full open access editorial for “Microbes and Alzheimer’s Disease” by Itzhaki, Ruth F.; Lathe, Richard; Balin, Brian J.; Ball, Melvyn J.; Bearer, Elaine L.; Bullido, Maria J.; Carter, Chris; Clerici, Mario; Cosby, S. Louise; Field, Hugh; Fulop, Tamas; Grassi, Claudio; Griffin, W. Sue T.; Haas, Jürgen; Hudson, Alan P.; Kamer, Angela R.; Kell, Douglas B.; Licastro, Federico; Letenneur, Luc; Lövheim, Hugo; Mancuso, Roberta; Miklossy, Judith; Lagunas, Carola Otth; Palamara, Anna Teresa; Perry, George; Preston, Christopher; Pretorius, Etheresia; Strandberg, Timo; Tabet, Naji; Taylor-Robinson, Simon D.; and Whittum-Hudson, Judith A. in Journal of Alzheimer’s Disease. Published online March 8 2016 doi:10.3233/JAD-160152


Microbes and Alzheimer’s Disease

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even though treatment based on it might slow or arrest AD progression. We refer to the many studies, mainly on humans, implicating specific microbes in the elderly brain, notably herpes simplex virus type 1 (HSV1), Chlamydia pneumoniae, and several types of spirochaete, in the etiology of AD. Fungal infection of AD brain [5, 6] has also been described, as well as abnormal microbiota in AD patient blood. The first observations of HSV1 in AD brain were reported almost three decades ago]. The ever-increasing number of these studies (now about 100 on HSV1 alone) warrants re-evaluation of the infection and AD concept.

AD is associated with neuronal loss and progressive synaptic dysfunction, accompanied by the deposition of amyloid-β (Aβ) peptide, a cleavage product of the amyloid-β protein precursor (AβPP), and abnormal forms of tau protein, markers that have been used as diagnostic criteria for the disease. These constitute the hallmarks of AD, but whether they are causes of AD or consequences is unknown. We suggest that these are indicators of an infectious etiology. In the case of AD, it is often not realized that microbes can cause chronic as well as acute diseases; that some microbes can remain latent in the body with the potential for reactivation, the effects of which might occur years after initial infection; and that people can be infected but not necessarily affected, such that ‘controls’, even if infected, are asymptomatic

“Microbes and Alzheimer’s Disease” by Itzhaki, Ruth F.; Lathe, Richard; Balin, Brian J.; Ball, Melvyn J.; Bearer, Elaine L.; Bullido, Maria J.; Carter, Chris; Clerici, Mario; Cosby, S. Louise; Field, Hugh; Fulop, Tamas; Grassi, Claudio; Griffin, W. Sue T.; Haas, Jürgen; Hudson, Alan P.; Kamer, Angela R.; Kell, Douglas B.; Licastro, Federico; Letenneur, Luc; Lövheim, Hugo; Mancuso, Roberta; Miklossy, Judith; Lagunas, Carola Otth; Palamara, Anna Teresa; Perry, George; Preston, Christopher; Pretorius, Etheresia; Strandberg, Timo; Tabet, Naji; Taylor-Robinson, Simon D.; and Whittum-Hudson, Judith A. in Journal of Alzheimer’s Disease. Published online March 8 2016 doi:10.3233/JAD-160152

Iron disorders , Vit B12, toxic drugs, and donating blood

Iron Disorders: The Importance of Checking Your Iron … – Dr. Mercola

Jun 12, 2016 – My dad has betathalassemia and he gave me the gene, which is a form of hemolytic anemia (similar to sickle cell anemia). As a result of that, my red blood cells die faster than normal, and I’m prone to excess iron. My dad had a ferritin level of 800 when I diagnosed him 20 years ago. He would be dead by …

Little-Known Secrets about Optimal Iron Levels – Dr. Mercola

Jul 14, 2009 – Acute blood loss; Other nutritional anemias, such as vitamin B12 or folic acid deficiencies; Cancer; Enlarged spleen; Genetic hemolytic anemias, such as sickle cell anemia, and thalassemia (also known as Mediterranean anemia), which I have. It’s a type of genetic anemia where the hemoglobin is not well …

Jun 5, 2013 – It was because he has betathalassemia. With regular phlebotomies, his iron levels normalized and now the only side effect he has is type 1 diabetes. The high iron levels damaged his pancreatic islet cells and now he has what is called “bronze” diabetes and so requires the use of insulin. I also inherited …

Why Managing Your Iron Level Is Crucial to Your Health – Dr. Mercola

May 31, 2017 – However, keep ALL iron supplements away from children, even carbonyl iron, and do not take any kind of iron supplement if you have hemochromatosis, hemosiderosis or hemolytic anemia such as sickle cell anemia or thalassemia (aka Mediterranean anemia, a type of genetic anemia where hemoglobin …

Missing: beta

How do You Know if You Are Anemic – Dr. Mercola

Jun 25, 2007 – Macrocytic anemia (macrocytic means large red blood cells) can be a sign of vitamin B-12 deficiency, and it may also be caused by folate deficiency. Folate deficiency is not common as it is in most raw vegetables, but some drugs (methotrexate and trimethoprim) and alcohol can cause it as can intolerance …

Conventional Heart Disease Advice May Make Matters … – Dr. Mercola

Aug 2, 2015 – On a side note, a novel point about coconut oil that many are unaware of is that for those of us, including myself, who suffer from a genetic condition called beta thalassemia — or chronic low cholesterol, which can be quite harmful — coconut oil can be used instead of drugs to raise your cholesterol.

Most Common Nutrient Deficiencies – Dr. Mercola

Oct 19, 2015 – It was because he has betathalassemia. With regular phlebotomies, his iron levels normalized, but the high iron levels damaged his pancreatic islet cells and now he has what is called “bronze” diabetes that requires the use of insulin. I inherited betathalassemia from him so I’m quite familiar with this issue …

Beginner Plan: Lifestyle Changes – Dr. Mercola

Over 20 years ago, through a simple test, I discovered that my dad had extremely high ferritin levels – close to 1,000 – due to a blood disorder called betathalassemia. If this had not been addressed, it would have been extremely fatal. Through regular phlebotomies, my dad’s iron levels have normalized, and the only side …

Understanding the Risks and Benefits of Beta-Blockers – Dr. Mercola

Aug 13, 2014 – Beta-blockers are drugs used in high blood pressure and congestive heart failure treatment, but now the ESC recommends it in non-cardiac surgery as well.

Missing: thalassemia

4 Unexpected Benefits of Donating Blood – Dr. Mercola

Jul 28, 2014 – I discovered he had a ferritin level close to 1,000. It was because he has betathalassemia. With regular phlebotomies, his iron levels normalized and now the only side effect he has is type 1 diabetes. His high iron levels damaged his pancreatic islet cells triggering what is called “bronze” diabetes, and so …

Mineral Nutrients Balance

Mineral Nutrients Balance

by Connie Dello Buono at

Iron Balance (am)

Calcium and Phosphorous Balance (pm)

Toxic metals Mercury, Arsenic , Lead , etc

Molybdenum and Manganese aid iron metabolim and lowers Copper and magnesium

Balance of Sodium, Potassium, Magnesium and  Calcium

Calcium lowers manganese

Calcium antagonist with Lead

Iron is lowered by Calcium and magnesium

Magnesium lowers sodium , potassium and manganese

Potassium lowers calcium and magnesium and synergistic with sodium

Phosphorus synergestic with calcium and antagonist with Manganese

Boron and Vitamin D aids in calcium and magnesium metabolism

Sulphur and copper lowers Selenium and zinc Selenium antagonistic with Mercury and arsenic

Calcium and Molybdenum and Silica

Calcium and Silica lowers Aluminum and Lead

Mercury lowers Silica
Copper, manganese and iron are synergistic

Zinc is lowered by Copper, calcium and Iron

Zinc has relationship with Aldosterone, cortisol, testosterone and progesterone Extra Copper and Manganese lowered by Zinc

Iodine has relationship with copper, selenium and magnesium

Lowered by mercury and cobalt

Omega 3, Vitamin D3 and Vitamin K2 aid in calcium and magnesium metabolism

Note: Vinegar and citrus help in the absorption of minerals in whole foods. Only 20% of iron are absorbed from plants and more than 35% are absorbed from animal based foods. Calcium and magnesium ratio is 60:40 . Nuts, beans and lentils and dark leafy greens , fish, seeds, shellfish , whole grains and mushrooms are tops in minerals