Intracellular Growth and Phagocytosis of Blastomyces dermatitidis by Monocyte-Derived Macrophages from Previously Infected and Normal Subjects

Bradsher, Robert W.; Ulmer, W. Clyde; Marmer, Daniel J.; Townsend, James W.; Jacobs, Richard F.

doi:10.1093/infdis/151.1.57

Cited by 21 publications

(7 citation statements)

References 13 publications

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“…While prior work supports the idea that B. dermatitidis may grow inside of host phagocytes in vitro (16), this and other work did not exclude the possibilities that phagocytes may repeatedly internalize yeast from the extracelluar environment, nor that phagocytes may fuse upon exposure to yeast. Each of these events could also result in the presence of multiple yeast in phagocytes and give the erroneous conclusion of intracellular replication.…”

Section: Introductionmentioning

confidence: 65%

“…Previous investigators have sought to evaluate intracellular replication of B. dermatitidis yeast within macrophages in vitro (16, 33). Their findings of an increase in CFU may have been confounded by the potential growth of extracellular or partially internalized yeast.…”

Section: Discussionmentioning

confidence: 99%

“…The larger yeast (10-30 μM) are also phagocytosed, but to a lesser extent and at a slower rate (11). Whereas spores are more vulnerable to killing by phagocytes, yeast can replicate in vitro in their presence, and electron microscopy has revealed multiple yeast inside human monocytes during co-culture (16). …”

Section: Introductionmentioning

confidence: 99%

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The Unappreciated Intracellular Lifestyle of Blastomyces dermatitidis

Sterkel

Mettelman

Wüthrich

et al. 2015

The Journal of Immunology

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Blastomyces dermatitidis, a dimorphic fungus and the causative agent of blastomycosis, is widely considered an extracellular pathogen, with little evidence for a facultative intracellular lifestyle. We infected mice with spores - the infectious particle - via the pulmonary route and studied intracellular residence, transition to pathogenic yeast and replication inside lung cells. Nearly 80% of spores were inside cells at 24 hours after infection with 104 spores. The majority of spores were located inside of alveolar macrophages, with smaller numbers in neutrophils and dendritic cells. Real time imaging showed rapid uptake of spores into alveolar macrophages, conversion to yeast, and intracellular multiplication during in vitro co-culture. The finding of multiple yeast in a macrophage was chiefly due to intracellular replication rather than multiple phagocytic events or fusion of macrophages. Depletion of alveolar macrophages curtailed infection in mice infected with spores, and lead to a 26-fold reduction in lung CFU by 6 days post-infection vs. non-depleted mice. Phase transition of the spores to yeast was delayed in these depleted mice over a time frame that correlated with reduced lung CFU. Spores cultured in vitro converted to yeast faster in the presence of macrophages than in medium alone. Thus, while advanced B. dermatitidis infection may exhibit extracellular residence in tissue, early lung infection with infectious spores reveals its unappreciated facultative intracellular lifestyle.

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Section: Introductionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

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The Unappreciated Intracellular Lifestyle of Blastomyces dermatitidis

Sterkel

Mettelman

Wüthrich

et al. 2015

The Journal of Immunology

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“…dermatitidis is a thermally dimorphic fungal pathogen with a wide geographic distribution, and it causes disease primarily in humans, dogs, and other mammals (1,3,4,6,8,20,21). B. dermatitidis resides in the environment as a saprophytic mold that forms infectious conidia that are aerosolized under the appropriate environmental conditions.…”

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confidence: 99%

Extracellular Calcium and Magnesium, but Not Iron, Are Needed for Optimal Growth ofBlastomyces dermatitidisYeast Form Cells In Vitro

Giles

Czuprynski

2004

Clin Vaccine Immunol

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In the present study, we demonstrate that the yeast form of Blastomyces dermatitidis can proliferate for short periods of time in the absence of ferric iron but not in the absence of calcium or magnesium. The results of this study shed light on the resistance of B. dermatitidis to chelating agents, such as deferoxamine, and may explain how B. dermatitidis resists the iron-binding activity of serum transferrin.

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“…Blastomycosis occurs following inhalation of B. dermatitidis conidia, which change into a pathogenic yeast form in the lungs. The resulting pulmonary infection can range in severity from mild to acute and can lead to disseminated disease (3,4,11,25). Relatively little is known about components of the innate immune system that limit the multiplication of the yeast form of B. dermatitidis during the early stages of infection.…”

mentioning

confidence: 99%

Novel Role for Albumin in Innate Immunity: Serum Albumin Inhibits the Growth ofBlastomyces dermatitidisYeast Form In Vitro

Giles

Czuprynski

2003

Infect Immun

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In this study we found that serum inhibitory activity against Blastomyces dermatitidis was principally mediated by albumin. This was confirmed in experiments using albumin from several mammalian species. Analbuminemic rat serum did not inhibit B. dermatitidis growth in vivo; however, the addition of albumin restored inhibitory activity. Inhibitory activity does not require albumin domain III and appears to involve binding of a low-molecular-weight yeast-derived growth factor.Blastomyces dermatitidis is a thermally dimorphic fungal pathogen that infects humans, dogs, and other mammals (2,4,11,26,27). Blastomycosis occurs following inhalation of B. dermatitidis conidia, which change into a pathogenic yeast form in the lungs. The resulting pulmonary infection can range in severity from mild to acute and can lead to disseminated disease (3,4,11,25). Relatively little is known about components of the innate immune system that limit the multiplication of the yeast form of B. dermatitidis during the early stages of infection.Innate immunity is mediated by several mechanisms that serve as important first lines of host defense against microbial pathogens. Human serum contains several factors (i.e., transferrin, lactoferrin, lysozyme, and complement) that can inhibit or kill pathogenic microorganisms. The inhibitory effect of serum on most pathogenic fungi is dependent on the ironbinding activity of transferrin, which is reported to inhibit the growth of Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, and Penicillium marneffei in vitro (1,19,20,27,(31)(32)(33)35). In a previous study, we demonstrated that serum inhibits B. dermatitidis yeast form growth in vitro via a mechanism that is independent of transferrin (12). Other prominent serum factors, such as complement components and natural antibodies, do not inhibit B. dermatitidis yeast form growth in vitro (13). In the present study, we sought to elucidate the identity of the serum factor that mediates inhibitory activity against B. dermatitidis.Preliminary experiments indicated that protein fractions smaller than 100 kDa possessed inhibitory activity against B. dermatitidis (data not shown). The most abundant protein present in these fractions was albumin. Although it seemed unlikely, we assessed whether albumin could exert inhibitory activity against B. dermatitidis. To do so, B. dermatitidis yeast cells were suspended in RPMI 1640 medium supplemented with fraction V bovine serum albumin (BSA; at 1 mg/ml, which is equivalent to the albumin concentration of 5% fetal bovine serum [FBS]), and viable yeast cells were quantified as described previously (12). To our surprise, we found that BSA inhibited the growth of B. dermatitidis yeast cells to an extent similar to that of 5% FBS (Fig. 1A). This activity was not restricted to BSA since human (Fig. 1B), mouse (Fig. 1C), and canine ( Fig. 1D) fraction V serum albumin proteins also significantly (P Ͻ 0.01) inhibited B. dermatitidis growth.These unexpected results prompted us to explore the novel possibili...

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Intracellular Growth and Phagocytosis of Blastomyces dermatitidis by Monocyte-Derived Macrophages from Previously Infected and Normal Subjects

Cited by 21 publications

References 13 publications

The Unappreciated Intracellular Lifestyle of Blastomyces dermatitidis

The Unappreciated Intracellular Lifestyle of Blastomyces dermatitidis

Extracellular Calcium and Magnesium, but Not Iron, Are Needed for Optimal Growth ofBlastomyces dermatitidisYeast Form Cells In Vitro

Novel Role for Albumin in Innate Immunity: Serum Albumin Inhibits the Growth ofBlastomyces dermatitidisYeast Form In Vitro

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