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Iron Overload Alters Innate and T Helper Cell Responses to Candida albicans in Mice
Abstract
The effect of iron overload on susceptibility of mice to Candida albicans infection and on the type of T helper (Th) immunity elicited was investigated. Iron overload greatly increased susceptibility to disseminated infection with low-virulence C. albicans cells of exogenous origin. The candidacidal activity and the ability to release nitric oxide and bioactive interleukin (IL)-12 were greatly impaired in neutrophils and macrophages from infected mice. CD4 T cells from spleens of iron-overloaded mice were found to produce high levels of IL-4 and IL-10 and low levels of interferon-gamma. Treatment of iron-overloaded mice with the iron chelator, deferoxamine, resulted in the cure of mice from infection, restored the antifungal effector and immunomodulatory functions of the phagocytic cells, and allowed the occurrence of CD4 Th1 protective antifungal responses. These data indicate that iron overload may negatively affect CD4 Th1 development in mice with candidiasis, a function efficiently restored by therapy with deferoxamine.
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“However, immune control of Candida infection could be restored by the iron chelator deferoxamine (DFO) (Mencacci et al., 1997).”
From Iron in infection and immunity (2020) · cites this paper as Mencacci et al., 1997
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Thus, macrophages loaded with iron lose their ability to clear infections with intracellular pathogens, such as Salmonella, Mycobacteria, Chlamydia, Candida, or Legionella (Mencacci et al., 1997; Chlosta et al., 2006; Nairz et al., 2007; Paradkar et al., 2008; Botella et al., 2012; Bellmann-Weiler et al., 2013) whereas reduction of iron levels or addition of iron chelators can improve infection”
From Iron at the interface of immunity and infection (2014) · cites this paper as Mencacci et al., 1997
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In the citing paper
“Iron overload in mice can hamper the protective Th1 response and ability to clear C. albicans infection (Mencacci et al., 1997; Ishida and Johansen, 2014).”
From Iron at the Centre of Candida albicans Interactions (2018) · cites this paper as Mencacci et al., 1997
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“This pathway appears to be partly responsible for the beneficial clinical effects of iron chelators observed in several experimental infection systems (Mencacci et al., 1997; Fritsche et al., 2001; Ibrahim et al., 2007; Bellmann-Weiler et al., 2013; Nairz et al., 2013).”
From Iron at the interface of immunity and infection (2014) · cites this paper as Mencacci et al., 1997
In the citing paper
“Inhibition of TFR affects the proliferation of T cell subtypes differently with TH1 immune responses being more sensitive to intracellular iron depletion than TH2 (Thorson et al., 1991; Mencacci et al., 1997).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Mencacci et al., 1997
In the citing paper
“Moreover, accumulation of intracellular Fe in T cells mitigates the activation, differentiation, and proliferation of T H 1 cells while fostering T H type 2 (T H 2) responses, as illustrated in the context of Candida albicans infection in mice [69,71].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [69]
In the citing paper
“Specifically, the intracellular Fe content of Mø modulates their response to interferon c (IFNc) [68,69], a cytokine produced by activated natural killer (NK) cells and T helper type 1 (T H 1) cells, which plays a central role in driving Mø microbicidal activity [70].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [69]
In the citing paper
“This is in a line with observation that iron supplementation skews T-cell differentiation towards a Th-2 response [130,131] which is largely referred to a negative regulatory effect of iron on the activity of the central Th-1 cytokine interferon-gamma (IFN-γ) [132].”
From Iron in immune cell function and host defense (2021) · cites this paper as [130]
In the citing paper
“On one hand, macrophage iron overload is associated with the inhibition of IFN-γ-driven antimicrobial immune effector pathways such as nitric oxide synthase 2 (Nos2) expression, resulting in impaired control of intracellular microbes (Weiss et al., 1994; Mencacci et al., 1997; Oexle et al., 2003).”
From Genetic and Dietary Iron Overload Differentially Affect the Course of Salmonella Typhimurium Infection (2017) · cites this paper as Mencacci et al., 1997
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- Romani L, Mencacci A, Cenci E, et al. Impaired neutrophil response and CD4 / Th1 development in IL-6 -deficient mice infected with Candida Whatever the mechanisms through which iron regulates Th albicans. J Exp Med 1996; 183:1345 -55.
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“This leads to induction of anti-inflammatory pathways and impaired control in numerous infectious diseases (72).”
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“Introduction Intravenous iron is an important part of the optimal treatment of anemia of ESRD (1), but it is biologically plausible that iron may increase infection risk by impairing neutrophil (2,3) and T cell function (4) and serving as a growth factor for pathogens (4,5).”
BackgroundIron and infection: Clinical experience
Hoen, B. (1999) · American Journal of Kidney Diseases · doi:10.1053/ajkd.1999.v34.aajkd0344b0030 · Cited by 45
Nairz, M., Schroll, A., Haschka, D., Dichtl, S., Tymoszuk, P., Demetz, E., Moser, P., Haas, H., Fang, F. C., Theurl, I., et al. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00110 · Cited by 46
“On one hand, macrophage iron overload is associated with the inhibition of IFN-γ-driven antimicrobial immune effector pathways such as nitric oxide synthase 2 (Nos2) expression, resulting in impaired control of intracellular microbes (Weiss et al., 1994; Mencacci et al., 1997; Oexle et al., 2003).”
BackgroundIron overload exacerbates experimental meningoencephalitis by Cryptococcus neoformans
Barluzzi, R., Saleppico, S., Nocentini, A., Boelaert, J. R., Neglia, R. G., Bistoni, F., & Blasi, E. (2002) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00324-7 · Cited by 44
Self-citationTsukamoto, H. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00772-9 · Cited by 43
Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases
Petzer, V., Theurl, I., & Weiß, G. (2018) · Pharmaceuticals · doi:10.3390/ph11040135 · Cited by 41
Pfeifhofer‐Obermair, C., Tymoszuk, P., Nairz, M., Schroll, A., Klais, G., Demetz, E., Engl, S., Brigo, N., & Weiß, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.637809 · Cited by 41
“This is in line with earlier studies indicating that Th1 T cells are exquisitely sensitive to iron perturbations because intracellular iron depletion affects Th1 cells more than the Th2 cell subset (8, 36, 37).”
BackgroundResultMolecular pathogenesis and clinical consequences of iron overload in liver cirrhosis
Sikorska, K., Bernat, A., & Wróblewska, A. (2016) · Hepatobiliary & pancreatic diseases international · doi:10.1016/s1499-3872(16)60135-2 · Cited by 41
Foster, S. L., Richardson, S. H., & Failla, M. L. (2001) · Journal of Nutrition · doi:10.1093/jn/131.5.1452 · Cited by 39
“Also, iron loading decreased the T helper-1/T helper-2 cytokine ratio and exacerbated the disease process in a murine model of candidiasis (19).”
BackgroundFrost, J. N., & Drakesmith, H. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-025-01193-y · Cited by 42
“Iron overload was found to impair T helper 1 (T H 1) cell responses in mouse Candida albicans and Salmonella enterica subsp. enterica serovar Typhimurium infection models 100,101 , whereas iron deficiency in anaemia impaired cytotoxic T cell responses to S. Typhimurium 102 .”
de Macedo, C. S., Lara, F. A., Pinheiro, R. O., Schmitz, V., Berrêdo‐Pinho, M., Pereira, G. M. B., & Pessolani, M. C. V. (2020) · F1000Research · doi:10.12688/f1000research.21383.1 · Cited by 38
Regulatory and pathogenic mechanisms in response to iron deficiency and excess in fungi
Pijuan, J., Moreno, D. F., Yahya, G., Moisa, M., Ul Haq, I., Krukiewicz, K., Mosbah, R., Metwally, K., & Cavalu, S. (2023) · Microbial Biotechnology · doi:10.1111/1751-7915.14346 · Cited by 37
“Contrarily, iron overload in the host results in more susceptibility towards Candida spp. infections, both superficial and systemic (Mencacci et al., 1997; Tripathi et al., 2022).”
BackgroundThe pathophysiology and treatment of Candida sepsis
Spellberg, B. J., & Edwards, J. E. (2002) · Current Infectious Disease Reports · doi:10.1007/s11908-002-0005-3 · Cited by 37
Vale-Costa, S., Gomes‐Pereira, S., Teixeira, C. M., Rosa, G. M., Rodrigues, P., Tomás, A. M., Appelberg, R., & Gomes, M. S. (2013) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0002061 · Cited by 35
“Additionally, delayed Th1 immune responses and Th2 phenotypes have been observed in response to iron supplementation in mice infected with Cryptoccocus neoformans [49] and Candida albicans [50], indicating that each particular hostpathogen interaction responds differently to iron overload.”
BackgroundBajbouj, K., Shafarin, J., Allam, H., Madkour, M. I., Awadallah, S. M., El-Serafi, A. T., Sandeep, D., & Hamad, M. A. (2018) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/s-0043-124077 · Cited by 36
Ghatrehsamani, M., Esmaeil, N., Soleimani, M., Asadi-Samani, M., Samani, K. G., & Shirzad, H. (2016) · Central European Journal of Immunology · doi:10.5114/ceji.2015.56973 · Cited by 36
“Iron overload also leads to natural killer (NK) cell dysfunction, impaired neutrophil cytotoxicity, changes in the ratio of CD4 to CD8 lymphocytes, impairs proliferative responses of helper and cytotoxic T cells and also affects MHC class II and intercellular adhesion molecule 1 [48, 49].”
BackgroundPyruvate kinase deficiency confers susceptibility to Salmonella typhimurium infection in mice
Roy, M.-F., Riendeau, N., Bédard, C., Hélie, P., Min-Oo, G., Turcotte, K., Gros, P., Canonne-Hergaux, F., & Malo, D. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20062606 · Cited by 35
Intravenous Iron and the Risk of Infection in End‐Stage Renal Disease Patients
Perazella, M. A., Brewster, U. C., & Perazella, M. A. (2004) · Seminars in Dialysis · doi:10.1111/j.1525-139x.2004.17115.x · Cited by 35
“Iron overload in mice decreased CD4 T-helper 1 development and increased susceptibility to Candida albicans infection (15).”
BackgroundChen, J., Lu, W., Zhao, M., Cao, X., Jiang, Y., Jin, X. K., Xu, P., Yuan, T., Zhang, Y., Chai, X., et al. (2017) · Annals of Hematology · doi:10.1007/s00277-017-2985-y · Cited by 35
Potential risk for infection and atherosclerosis due to iron therapy
Sengoelge, G., Sunder–Plassmann, G., & Hörl, W. H. (2005) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2004.09.018 · Cited by 32
Hematology of malnutrition, part one
Jacobs, P., & Wood, L. (2003) · Disease-a-Month · doi:10.1016/s0011-5029(03)00131-7 · Cited by 33
Intracellular microbes and haemophagocytosis
Silva‐Herzog, E., & Detweiler, C. S. (2008) · Cellular Microbiology · doi:10.1111/j.1462-5822.2008.01192.x · Cited by 31
“, 2007), or by affecting T-cell activation (Mencacci et al., 1997).”
BackgroundŠpaček, J., Jílek, P., Buchta, V., Förstl, M., Hronek, M., & Holečková, M. (2005) · Mycoses · doi:10.1111/j.1439-0507.2005.01164.x · Cited by 32
Ferroptosis of T cell in inflammation and tumour immunity
Xia, X., Wu, H., Chen, Y., Peng, H., & Wang, S. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70253 · Cited by 34
Hoffmann, A., Haschka, D., de Souza, L. V., Tymoszuk, P., Seifert, M., von Raffay, L., Hilbe, R., Petzer, V., Moser, P. L., Nairz, M., et al. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103568 · Cited by 31
“This would be in line with effects of iron restriction on IFNg formation and Th1 expression and improved immune control of infection [59,81,82].”
BackgroundTherapy by taking away: the case of iron
Polla, B. S. (1999) · Biochemical Pharmacology · doi:10.1016/s0006-2952(99)00017-9 · Cited by 31
HEMATOLOGY: ISSUES IN THE DIALYSIS PATIENT: Intravenous Iron Therapy in End‐Stage Renal Disease
Brewster, U. C. (2006) · Seminars in Dialysis · doi:10.1111/j.1525-139x.2006.00174.x · Cited by 30
“Experimental ironoverloaded mice had decreased CD4-helper-1 cell development and increased susceptibility to Candida albicans infection (20).”
BackgroundA functional defect in hereditary haemochromatosis monocytes and monocyte‐derived macrophages
Moura, Verheul, & Marx, J. J. M. (1998) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.1998.00263.x · Cited by 30
Neutrophils and the adaptive immune response to Candida albicans
Romani, L. R., Mencacci, A., Cenci, E., Puccetti, P., & Bistoni, F. (1996) · Research in Immunology · doi:10.1016/s0923-2494(97)85216-9 · Cited by 30
Self-citationHaschka, D., Nairz, M., Demetz, E., Wienerroither, S., Decker, T., & Weiss, G. (2015) · Metallomics · doi:10.1039/c4mt00328d · Cited by 29
Cytokine mRNA Expression and Iron Status in Children Living in a Malaria Endemic Area
Nyakeriga, A. M., Williams, T. N., Marsh, K., Wambua, S., Perlmann, H., Perlmann, P., Grandien, A., & Troye‐Blomberg, M. (2005) · Scandinavian Journal of Immunology · doi:10.1111/j.1365-3083.2005.01573.x · Cited by 28
Xu, Y., Feng, Y., Li, H., & Gao, Z. (2012) · Food and Chemical Toxicology · doi:10.1016/j.fct.2012.05.061 · Cited by 25
Li, G., Pone, E. J., Tran, D. C., Patel, P. J., Dao, L., Xu, Z., & Casali, P. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.366732 · Cited by 25
“Consistent with the principle outlined here by our in vitro findings, high iron levels are associated in different contexts with impaired antibody responses (25, 46).”
Metadata
- Authors
- Mencacci, A., Cenci, E., Boelaert, J. R., Bucci, P., Mosci, P., d'Ostiani, C. F., Bistoni, F., & Romani, L.
- Affiliations
- University of Perugia (IT)
- Venue
- The Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 1997-06
- Volume
- 175
- Issue
- 6
- Pages
- 1467-1476
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- OpenAlex
- W2150374661
- Semantic Scholar
- 599845e36faeaa77f8bb9150b69754059dcae780
- Cited by
- 169
- References
- 57
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 6 · 2020: 10 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 6 · 2015: 7 · 2014: 4 · 2013: 9 · 2012: 8
- FWCI
- 6.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- iron overload, Candida albicans, candidiasis, deferoxamine, iron chelation, Th1 cells, CD4+ T cells, neutrophils, macrophages, nitric oxide, IL-12, IL-4, IL-10, interferon-gamma, antifungal immunity, disseminated fungal infection, immunomodulation
- MeSH terms
- Animals, Candida albicans, Candidiasis, Deferoxamine, Disease Susceptibility, Ferric Compounds, Immunoglobulin E, Iron, Iron Chelating Agents, Kidney, Liver, Macrophages, Mice, Inbred BALB C, Neutrophils, Nitrates, Nitric Oxide, RNA, Gene Expression, Cytokines, Th1 Cells, Nitric Oxide Synthase, Iron Overload, Mice
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