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IRON: Bacterial, Fungal, Viral, Protozoan Infections and infectious Processes

As on other Science Library pages, we do not present a lengthy narrative on each body system affected by infection, but rather will briefly summarize or quote the most relevant take-home points and/or research conclusions from each study. Article titles are linked to abstracts archived at the U.S. National Library of Science. Many articles also have Full free text PDF links. Our Iron Science Library pages include:

 


Iron availability and infection (1)

In this 2009 review of the literature the author notes that, "To successfully sustain an infection, nearly all bacteria, fungi and protozoa require a continuous supply of host iron." "Mechanisms of microbial iron acquisition are determinants for the kinds of cells, tissues and hosts in which pathogens can flourish." And with respect to human and other "hosts," "As a corollary, hosts possess an array of iron withholding devices whereby they can suppress or abort microbial invasions." "Awareness of environmental and behavioral methods that can prevent iron loading plus development of pharmaceutical agents that can block microbial access to iron may help to reduce our dependence on antibiotics."

 

Iron loading and disease surveillance (2) Free full paper

This 1999 review and the accompanying full paper describe, "Iron is an oxidant as well as a nutrient for invading microbial and neoplastic cells. Excessive iron in specific tissues and cells (iron loading) promotes development of infection, neoplasia, cardiomyopathy, arthropathy, and various endocrine and possibly neurodegenerative disorders. To contain and detoxify the metal, hosts have evolved an iron withholding defense system, but the system can be compromised by numerous factors. An array of behavioral, medical, and immunologic methods are in place or in development to strengthen iron withholding. Routine screening for iron loading could provide valuable information in epidemiologic, diagnostic, prophylactic, and therapeutic studies of emerging infectious diseases." [Health-e-Iron note: Tables 1 and 2 from this paper appear below]

 


Circulating Biomarkers of Iron Storage and Clearance of Incident Human Papillomavirus Infection (3) Free full text

The researchers in this 2012 study provided this background and hypothesis: "Iron is an essential mineral for both cellular and pathogen survival and is essential for viral replication. In turn, iron metabolism has been shown to be altered by several viral infections. However, little is known regarding the association between iron status and HPV natural history. We hypothesize iron to be an HPV-cofactor that is associated with longer duration of infection."  "Ferritin and soluble transferrin receptor (sTfR) were measured in baseline serum samples from 327 women." "Women with ferritin levels above the median were less likely to clear an incident oncogenic HPV... and HPV-16 infections ... Using physiological cut-points, women with enriched iron stores (>120dg/mL) were less likely to clear incident oncogenic HPV infections compared to those with low-levels of iron (<20dgm/L)( AHR=0.34; 95%CI 0.15-0.81). the researchers concluded, "This study observed that women with the highest ferritin levels were less likely to clear incident oncogenic and HPV-16 infections compared to women with low ferritin. Rising iron stores may decrease probability of clearing new HPV infection, possibly by promoting viral activity and contributing to oxidative DNA damage. Impact: This novel study suggests that elevated iron stores may put women at risk for persistent HPV infection, an early event in cervical carcinogenesis. Further examination of the association between iron status and HPV natural history is warranted."

 

Histoplasma capsulatum secreted gamma-glutamyltransferase reduces iron by generating an efficient ferric reductant (4) Free full text

In this 2008 study the University of Wisconsin note, "The intracellular fungal pathogen Histoplasma capsulatum (Hc) resides in mammalian macrophages and causes respiratory and systemic disease. Iron limitation is an important host antimicrobial defense, and iron acquisition is critical for microbial pathogenesis. Hc displays several iron acquisition mechanisms, including secreted glutathione-dependent ferric reductase activity (GSH-FeR). Observations from this laboratory study provide insight into the biological process that this pathogen employes through GGT expression and the consequent reduction of ferric iron to highly catalytic ferrous iron, a process that promotes the survival and growth of this fungal pathogen." [Health-e-Iron note: for those unfamiliar with the context of the word "reduces" in relation to iron, it does not mean a reduction in the quantity of iron, but rather it refers to to a change of iron molecules from a relatively benign state to a potentially highly toxic one that can promote dangerous biochemical reactions within the body including oxidative damage, the production of free radicals and the growth of many pathogens]


Ferritin as an Iron Source for Pathogens (5) Free full text* (see below)

[Health-e-Iron note*: the publishers of this 2012 book have make this chapter available as a "Free Access" document. If you link to the abstract you can access the full text in a PDF format. However there are restrictions covering duplication of the material contained therein, and we may not store the document on our web site, nor replicate some of the tables contained in the chapter] The authors describe how some pathogens are able to destroy cells and tissue and gain "easy access to ferritin and make use of its iron." "Due to the high amount of iron atoms that ferritin is able to capture, this protein is really a remarkable iron source for every intracellular pathogen." "In the literature, there are only a few reports about pathogens using ferritin as an iron source, but this is an exciting growing field of research. Each pathogen has developed its own manner to obtain iron from ferritin:.." The authors describes the various mechanisms by which many different pathogenic invaders can free iron from ferritin. Table 1 starting on page 5 of this chapter cites the scientific names of  10 such microorganism (8 bacteria, 2 parasite and 1 fungi), the known iron acquisition systems from ferritin and the tissue or organ sites where the microorganisms obtain ferritin. We have reproduced parts of this table below the scientific names of the microorganisms, their common names and the tissue or organ sites where ferritin is obtained:

 

Microorganism
Common Name or related illness

Tissue of Organ Site where microorganism obtains ferritin

 Bacteria    
Bacillus cereus
 food sickness
 intestinal cells, oral epithelium, retinal tissue, CNS, blood, liver, striated muscle, skin, heart tricuspid-valve
Burkholderia cenocepacia
common in cystic fibrosis and granulomatous diseases
 Lungs, macrophages, epithelial cells
Escherichia coli, and Yersinia pestis

1. E. coli    2. the plagues

 E. coli: intestinal cells, urinary tract, kidneys, CNS, blood

Yerisinia pestis: blood, lungs, lymph nodes, macrophages

Listeria monocytogenes
Listeria  Intestinal cells, macrophages, hepatocytes, epithelial cells, fibroblasts, endothelial cells, neurons
Mycrobacterium spp
non- tuberculosis mycrobacterium
 Lungs, macrophages
 Neisseria meningitidis
 meningococcal diseases  Respiratory tract, blood, CNS
Streptococcus pyogenes
Group A Strep infections
 Lungs, throat, epithelium, skin
 Parasite    
Entamoeba histolytica
Protozoan infection
 Blood, brain, instestinal cell, hepatocyte, lungs
Trichomonas vaginalis
Sexually transmitted infection
 Vaginal muscosa
 Fungi    
Candida albicans
Yeast infection
 Vaginal, oral-pharyngeal, and gastrointestinal mucosae; blood, CNS, internal organs like lungs and heart

 

Iron availability increases the pathogenic potential of Salmonella typhimurium and other enteric pathogens at the intestinal epithelial interface (5) Free full text

Reported in 2012, this research team noted, "Recent trials have questioned the safety of untargeted oral iron supplementation in developing regions. Excess of luminal iron could select for enteric pathogens at the expense of beneficial commensals in the human gut microflora, thereby increasing the incidence of infectious diseases." The researchers observed in this laboratory study that, "Growth of Salmonella typhimurium and other enteric pathogens was increased in response to iron." The researchers concluded, "our data fit with the consensus that oral iron supplementation is not without risk as iron could, in addition to inducing pathogenic overgrowth, also increase the virulence of prevalent enteric pathogens." [Health-e-Iron note: Figure 1 and Table 2 from this research appear below]

Figure 1. Effect of iron on growth of enteric bacteria. Effect of various concentrations of ferric citrate on in vitro growth of (A) S. typhimurium, (B) C. freundii, (C) E. coli, (D) E. faecalis and (E) L. plantarum. 

 

Figure 2. Effect of iron on bacterial adhesion to an epithelial monolayer. Adhesion (mean+SD) of enteric bacteria to a monolayer of Caco-2 cells is given as percentage of the inoculum. A: S. typhimurium, n=8. B: C. freundii, n=4. C: E. coli, n=6. D: E. faecalis, n=6. E: L. plantarum, n=5. Means without a common letter differ, P,0.05. Notably, adhesion data of S. typhimurium were derived from 4 separate experiments performed at 13, 15, 18 and 21 days post-seeding of Caco-2 cells. The fact that each experiment revealed the same trend is indicative for similar physiochemical properties of the monolayer at these time points. 

 

Regulatory interactions for iron homeostasis in Aspergillus fumigatus inferred by a Systems Biology approach (6) Free full paper

The researchers in this 2012 study noted, "Aspergillus fumigatus is a major human fungal pathogen. One important virulence trait is its ability to gain sufficient amounts of iron during infection process. Even though some regulatory interactions are known, we are still far from a complete understanding of the way iron homeostasis is regulated." In this paper the researcher employ a Systems Biology approach (an interlocking circle between experimental and theoretical work) to deduce the role of iron metabolism in several pathogens.

 

Hepatic iron overload is common in chronic hepatitis B and is more severe in patients coinfected with hepatitis D virus (7)

In this 2012 study from Italy the researchers noted, "Hepatic iron overload has been described in chronic hepatitis C as a cofactor affecting fibrosis progression. Data in patients with chronic hepatitis B infection are scarce. We investigated hepatic iron deposits and serum iron indices in 205 consecutive patients with hepatitis B and compensated liver disease. Mean age of the patients was 42.4 ± 12.4 years and 72.5% were males." "Hepatic iron deposits were detected in 35.1% of patients, most of them being minimal (grade I) (59.7%) or mild (grade II) (27.8%). Variables significantly associated with hepatic iron deposits were male gender (P = 0.001), serum ferritin (P = 0.008), GGT (P = 0.05) and alkaline phosphatase (P = 0.05) levels." "A significant correlation between coinfection with HDV and hepatic iron deposits was also found (OR 4.23, 95% CI 1.52-11.82, P = 0.003). When compared to monoinfected cases, HDV positive patients had more elevated GGT (P = 0.03), more advanced fibrosis and more severe iron deposits (P < 0.0001)." "In conclusion, in well-compensated chronic hepatitis B infection, hepatic iron deposits and elevation of serum iron indices are common, especially in male gender and in patients coinfected with HDV. As HBV/HDV liver disease is generally more rapidly progressive than that caused by HBV monoinfection, we speculate that iron overload may be one of the factors contributing to the severity of liver disease."


Gastrointestinal, hepatobiliary, pancreatic, and iron-related diseases in long-term survivors of allogeneic hematopoietic cell transplantation (8)

This 2012 review from the Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine discusses the potent aftereffects of iron overload following stem cell transplantation. "As time passes, as tolerance develops, and as immunity improves, the frequency and severity of these problems wane, but new problems involving the gut and liver may arise, sometimes insidiously and sometimes decades after the transplant. Examples are esophageal strictures related to chronic GVHD, gallstones, cirrhosis caused by chronic hepatitis C, secondary malignancy, and rare cases of pancreatic atrophy." "One very common complication of transplantation, iron overload, is often associated with substantial iron accumulation in the liver; however, the most troublesome complications are not hepatic but cardiac and endocrine-related." [Health-e-Iron note: mild to significant degrees of iron overload create a major concern for organ transplant candidates and recipients. We will be adding a page to this web site dedicated to this topic. High iron levels in persons with compromised immune systems present significant infection risks -- these risks are heightened during hospitalizations] 


Siderophore-mediated iron acquisition in the staphylococci (9)

This is a 2010 review of the uptake mechanisms utilized by staphylococci to obtain iron molecules from animal hosts.

 

Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy (10)

In this large 2012 European study the researchers reported, "...serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N = 970), fibrosis (N = 980), steatosis (N = 886), and response to treatment (N = 876)." "We found that serum ferritin ≥ the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.34-0.60). This association remained highly significant in a multivariate analysis (P = 0.0002, OR = 0.35, 95% CI = 0.20-0.61)..." "Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR = 2.67, 95% CI = 1.68-4.25) and steatosis (P = 0.002, OR = 2.29, 95% CI = 1.35-3.91), but not with necroinflammatory activity (P = 0.3).  The researchers concluded, "In patients with CHC (chronic hepatitis C), elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy."

 

The determination of GGT is the most reliable predictor of nonresponsiveness to interferon-alpha based therapy in HCV type-1 infection  (11)

Similar to the paper direct above, this 2011 study reported in Germany noted that GGT is also a strong predictor of nonresponsiveness to standard HCV treatment. The researchers noted, "The critical analysis of baseline factors has been found to be useful to predict virologic nonresponse (NR), relapse, or sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) who receive antiviral therapy. In the present retrospective study we tried to find out whether gamma-glutamyltranspeptidase (GGT) may be one of the baseline factors which are of special predictive power. We analyzed, in patients with different treatment outcomes, the predictive power of established baseline factors either in combination with GGT or by evaluating the predictive value of GGT independently" "Individual data from 632 patients chronically infected with HCV type 1 (n = 561) or type 2/3 (n = 71) were analyzed. All patients had received their first course of antiviral therapy and were treated with pegylated interferon α-2a or -2b plus ribavirin." "In patients with HCV type 1, a multivariate multinomial logistic regression analysis identified low GGT (p < 0.0001), high cholesterol (p < 0.0001), age ≤ 40 years (p < 0.0001), high alanine aminotransferase (p = 0.0006), low viremia (p = 0.0014), and absence of cirrhosis (p = 0.0164) as independent predictors. While these baseline factors heralded improved virologic response, high GGT, in contrast, was significantly associated with NR (p < 0.0001). A strong correlation was found between log(10) GGT and a scoring variable S (r = -0.26 for prediction of SVR, p < 0.001; r = 0.11 for prediction of NR, p = 0.016) summarizing predictive information from other baseline factors." The researchers concluded, "These findings prove the predictive sensitivity of GGT as an independent indicator of nonresponsiveness even at levels that are slightly above the normal range. This new predictive parameter may help to improve individualized therapy in HCV type-1 infection."


Enhanced iron availability by protein glycation may explain higher infection rates in diabetics (12)

This 2012 laboratory study done in California reported, "The results, in addition to data in the literature, support the hypothesis that glycation of serum proteins may effectively increase the available free iron pool for bacteria in blood serum and weaken our innate immunity. This phenomenon may be partially responsible for higher infection rates in some diabetics, especially those with poor glycemic control."

 

Iron and acetaminophen a fatal combination? (13) Free full text

Related to infection and other damage processes, this 2011 report from the U.K. states, "Intentional iron overdose in adults is uncommon. Clinical consequences are variable and depend on the quantity of iron ingested and the delay to treatment. Severe iron overdose can lead to multi-organ failure and acute hepatic necrosis. Here, we report three cases of polypharmacy overdose including iron resulting in acute liver failure. Despite maximum supportive care including liver transplantation in two cases, all patients died. Iron poisoning may have an additive toxic effect in drug-induced acute liver failure and worsen outcome."

 

Iron homeostasis--Achilles' heel of Aspergillus fumigatus? (14) Free full text

In this 2011 research from Austrian investigators, an interesting hypothesis is explored, "The opportunistic fungal pathogen Aspergillus fumigatus adapts to iron limitation by upregulation of iron uptake mechanisms including siderophore biosynthesis and downregulation of iron-consuming pathways to spare iron. These metabolic changes depend mainly on the transcription factor HapX. Consistent with the crucial role of iron in pathophysiology, genetic inactivation of either HapX or the siderophore system attenuates virulence of A. fumigatus in a murine model of aspergillosis. The differences in iron handling between mammals and fungi might serve to improve therapy and diagnosis of fungal infections." [Health-e-Iron note: Figures 1 and 2 from this research appear below]

A. fumigatus mechanisms for iron uptake and storage. (a) Schematic summary of iron uptake and storage mechanisms. (b) Siderophore structures. R = H in FsC and R = acetyl in TAFC; the hydroxylation site in FC is unknown. (c) Siderophore biosynthetic pathway. See text for details.

 

Increased bone marrow iron stores is an independent risk factor for invasive aspergillosis in patients with high-risk hematologic malignancies and recipients of allogeneic hematopoietic stem cell transplantation (15) Free full text

This 2007 study was published by the Department of Infectious Diseases, Infection control, and Employee Health at the M.D. Anderson Cancer Center. The researchers noted "Invasive aspergillosis (IA) is a leading cause of death in patients with leukemia and those who have undergone hematopoietic stem cell transplantation. Laboratory studies have demonstrated that iron is essential for Aspergillus growth and virulence." "In the current study, the authors retrospectively evaluated the bone marrow iron stores (BMIS) in patients with leukemia as well as recipients of allogeneic hematopoietic stem cell transplantation with IA (n = 33) and those without fungal infections (n = 33). The first available bone marrow biopsy specimens prior to the IA diagnosis or date of hospitalization (control group) were assessed in a blinded fashion using a standardized scoring system (0-4). Both groups were comparable with regard to clinical characteristics and classic risk factors for IA." "The majority of patients with IA (70%) were found to have increased BMIS (score >or=3) compared with the control patients (16%) (P < .0001). Increased BMIS was found to be an independent risk factor for IA on multivariate analysis (P < .0001)." The researchers concluded, "The prospective validation of BMIS for risk stratification in patients with leukemia or those who undergo allogeneic hematopoietic stem cell transplantation is needed."

 

Fatal laboratory-acquired infection with an attenuated Yersinia pestis Strain--Chicago, Illinois, 2009 (16) Free full text

The CDC published this report in 2011 on a widely publicize event that occurred in 2009 when a laboratory worker died after contact with an attenuated strain of Yersinia pestis (the "plague"). The patient was later found out to have undiagnosed hereditary hemochromatosis (HHC). The CDC hypothesized, "One possible explanation for the unexpected fatal outcome in this patient is that hemochromatosis-induced iron overload might have provided the infecting KIM D27 strain, which is attenuated as a result of defects in its ability to acquire iron, with sufficient iron to overcome its iron-acquisition defects and become virulent."

 

Increased serum iron levels and infectious complications after liver transplantation (17) Free full text

This 2010 study the researchers noted, "Elevated serum iron levels have been associated with infectious outcomes in various patient populations but, to our knowledge, have never been studied after liver transplantation." "Unadjusted and adjusted hazard ratios were calculated for each iron marker predictor variable (iron level, unsaturated iron-binding capacity, total iron-binding capacity, transferrin saturation, and ferritin level) and time to development of each of 6 outcomes (cytomegalovirus [CMV] disease, invasive fungal infection, bacteremia, invasive fungal infection or bacteremia, any infection, and 1-year mortality rate)." "Serum measurements (n = 109) corresponding to increased levels of serum iron were independently associated with an increased risk of any infection and death. After adjusting for the number of red blood cell transfusions, donor CMV-seropositive status, and fungal colonization, ferritin level was independently associated with the development of any infection (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14). After adjusting for the number of red blood cell transfusions, development of CMV disease, and administration of intravenous steroids for treatment of rejection, ferritin level was also was independently associated with death (hazard ratio, 1.11; 95% confidence interval, 1.04-1.18). Similar results were found for unsaturated iron binding capacity for the same 2 outcomes." [Health-e-Iron note: Tables 2 and 3 from this research appear below. Note form the tables below, infections versus no infections occurred in patients having comparatively higher mean transferrin saturation by 15%  and higher mean ferritin by 48%. Person who died compared to those with no infections had relative increased transferrin saturation by 42% and increased ferritin by 64%.]


Association of γ-glutamyl transferase (GGT) activity with treatment and clinical outcomes in chronic hepatitis C (HCV)  Free full text

This was a 2013-reported study from the HALT-C Study in the US. The investigators noted, "We examined GGT as a predictor of both virological response to treatment and long-term clinical outcomes in the Hepatitis C Anti-viral Treatment Against Cirrhosis Trial (HALT-C). HALT-C enrolled patients with advanced liver disease (Ishak fibrosis score ≥3) in two phases: a lead-in to establish lack of sustained viral response with full dose pegylated interferon (IFN) and ribavirin followed by a 3.5-year randomized trial with low-dose IFN. Low-dose IFN did not prevent liver disease progression, and patients were then followed for up to an additional 5 years off therapy. Analyses were performed for 1,319 patients who had GGT measured prior to initiation of treatment. Increases in risk with each increase in quintile of GGT (10-57, 58-89, 90-139, 140-230, 231-2,000 IU/L) were determined by logistic regression for treatment response or Cox regression for clinical outcomes. Baseline GGT was associated with male sex, nonwhite ethnicity, diabetes and insulin resistance, interleukin (IL)28B rs12979860 CT and TT genotypes, and numerous markers of liver disease injury and severity. In the lead-in phase, increasing GGT was strongly associated with diminished week 20 response, end of treatment response, and sustained virological response in both univariate and multivariate analyses controlling for factors known to be associated with treatment response (P < 0.0001). GGT was also associated with all clinical outcomes in univariate and multivariate analysis (P < 0.05) except for hepatocellular carcinoma (P = 0.46 in multivariate analysis). Conclusion: GGT is an independent predictor of both virological response and clinical outcomes among patients with advanced liver disease due to HCV."