Human Serum Albumin Facilitates Heme-Iron Utilization by Fungi

ABSTRACT A large portion of biological iron is found in the form of an iron-protoporphyrin IX complex, or heme. In the human host environment, which is exceptionally poor in free iron, heme iron, particularly from hemoglobin, constitutes a major source of iron for invading microbial pathogens. Sever...

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Autores principales:	Mariel Pinsky, Udita Roy, Shilat Moshe, Ziva Weissman, Daniel Kornitzer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Candida albicans heme transport iron acquisition mycology Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/567c8e8d6a5b475f89041c9a98f5876a
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spelling	oai:doaj.org-article:567c8e8d6a5b475f89041c9a98f5876a2021-11-15T15:57:03ZHuman Serum Albumin Facilitates Heme-Iron Utilization by Fungi10.1128/mBio.00607-202150-7511https://doaj.org/article/567c8e8d6a5b475f89041c9a98f5876a2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00607-20https://doaj.org/toc/2150-7511ABSTRACT A large portion of biological iron is found in the form of an iron-protoporphyrin IX complex, or heme. In the human host environment, which is exceptionally poor in free iron, heme iron, particularly from hemoglobin, constitutes a major source of iron for invading microbial pathogens. Several fungi were shown to utilize free heme, and Candida albicans, a major opportunistic pathogen, is able both to capture free heme and to extract heme from hemoglobin using a network of extracellular hemophores. Human serum albumin (HSA) is the most abundant host heme-scavenging protein. Tight binding of heme by HSA restricts its toxic chemical reactivity and could diminish its availability as an iron source for pathogenic microbes. We found, however, that rather than inhibiting heme utilization, HSA greatly increases availability of heme as an iron source for C. albicans and other fungi. In contrast, hemopexin, a low-abundance but high-affinity heme-scavenging serum protein, does inhibit heme utilization by C. albicans. However, inhibition by hemopexin is mitigated in the presence of HSA. Utilization of albumin-bound heme requires the same hemophore cascade as that which mediates hemoglobin-iron utilization. Accordingly, we found that the C. albicans hemophores are able to extract heme bound to HSA in vitro. Since many common drugs are known to bind to HSA, we tested whether they could interfere with heme-iron utilization. We show that utilization of albumin-bound heme by C. albicans can be inhibited by the anti-inflammatory drugs naproxen and salicylic acid. IMPORTANCE Heme constitutes a major iron source for microorganisms and particularly for pathogenic microbes; to overcome the iron scarcity in the animal host, many pathogenic bacteria and fungi have developed systems to extract and take up heme from host proteins such as hemoglobin. Microbial heme uptake mechanisms are usually studied using growth media containing free heme or hemoglobin as a sole iron source. However, the animal host contains heme-scavenging proteins that could prevent this uptake. In the human host in particular, the most abundant serum heme-binding protein is albumin. Surprisingly, however, we found that in the case of fungi of the Candida species family, albumin promoted rather than prevented heme utilization. Albumin thus constitutes a human-specific factor that can affect heme-iron utilization and could serve as target for preventing heme-iron utilization by fungal pathogens. As a proof of principle, we identify two drugs that can inhibit albumin-stimulated heme utilization.Mariel PinskyUdita RoyShilat MosheZiva WeissmanDaniel KornitzerAmerican Society for MicrobiologyarticleCandida albicansheme transportiron acquisitionmycologyMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans heme transport iron acquisition mycology Microbiology QR1-502
spellingShingle	Candida albicans heme transport iron acquisition mycology Microbiology QR1-502 Mariel Pinsky Udita Roy Shilat Moshe Ziva Weissman Daniel Kornitzer Human Serum Albumin Facilitates Heme-Iron Utilization by Fungi
description	ABSTRACT A large portion of biological iron is found in the form of an iron-protoporphyrin IX complex, or heme. In the human host environment, which is exceptionally poor in free iron, heme iron, particularly from hemoglobin, constitutes a major source of iron for invading microbial pathogens. Several fungi were shown to utilize free heme, and Candida albicans, a major opportunistic pathogen, is able both to capture free heme and to extract heme from hemoglobin using a network of extracellular hemophores. Human serum albumin (HSA) is the most abundant host heme-scavenging protein. Tight binding of heme by HSA restricts its toxic chemical reactivity and could diminish its availability as an iron source for pathogenic microbes. We found, however, that rather than inhibiting heme utilization, HSA greatly increases availability of heme as an iron source for C. albicans and other fungi. In contrast, hemopexin, a low-abundance but high-affinity heme-scavenging serum protein, does inhibit heme utilization by C. albicans. However, inhibition by hemopexin is mitigated in the presence of HSA. Utilization of albumin-bound heme requires the same hemophore cascade as that which mediates hemoglobin-iron utilization. Accordingly, we found that the C. albicans hemophores are able to extract heme bound to HSA in vitro. Since many common drugs are known to bind to HSA, we tested whether they could interfere with heme-iron utilization. We show that utilization of albumin-bound heme by C. albicans can be inhibited by the anti-inflammatory drugs naproxen and salicylic acid. IMPORTANCE Heme constitutes a major iron source for microorganisms and particularly for pathogenic microbes; to overcome the iron scarcity in the animal host, many pathogenic bacteria and fungi have developed systems to extract and take up heme from host proteins such as hemoglobin. Microbial heme uptake mechanisms are usually studied using growth media containing free heme or hemoglobin as a sole iron source. However, the animal host contains heme-scavenging proteins that could prevent this uptake. In the human host in particular, the most abundant serum heme-binding protein is albumin. Surprisingly, however, we found that in the case of fungi of the Candida species family, albumin promoted rather than prevented heme utilization. Albumin thus constitutes a human-specific factor that can affect heme-iron utilization and could serve as target for preventing heme-iron utilization by fungal pathogens. As a proof of principle, we identify two drugs that can inhibit albumin-stimulated heme utilization.
format	article
author	Mariel Pinsky Udita Roy Shilat Moshe Ziva Weissman Daniel Kornitzer
author_facet	Mariel Pinsky Udita Roy Shilat Moshe Ziva Weissman Daniel Kornitzer
author_sort	Mariel Pinsky
title	Human Serum Albumin Facilitates Heme-Iron Utilization by Fungi
title_short	Human Serum Albumin Facilitates Heme-Iron Utilization by Fungi
title_full	Human Serum Albumin Facilitates Heme-Iron Utilization by Fungi
title_fullStr	Human Serum Albumin Facilitates Heme-Iron Utilization by Fungi
title_full_unstemmed	Human Serum Albumin Facilitates Heme-Iron Utilization by Fungi
title_sort	human serum albumin facilitates heme-iron utilization by fungi
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/567c8e8d6a5b475f89041c9a98f5876a
work_keys_str_mv	AT marielpinsky humanserumalbuminfacilitateshemeironutilizationbyfungi AT uditaroy humanserumalbuminfacilitateshemeironutilizationbyfungi AT shilatmoshe humanserumalbuminfacilitateshemeironutilizationbyfungi AT zivaweissman humanserumalbuminfacilitateshemeironutilizationbyfungi AT danielkornitzer humanserumalbuminfacilitateshemeironutilizationbyfungi
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Human Serum Albumin Facilitates Heme-Iron Utilization by Fungi

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