Macrophage- and Oxidant-Mediated Inhibition of the Ability of Live Blastomyces dermatitidis Conidia to Transform to the Pathogenic Yeast Phase: Implications for the Pathogenesis of Dimorphic Fungal Infections

Sugar, Alan M.; Picard, Michele

doi:10.1093/infdis/163.2.371

Cited by 35 publications

(14 citation statements)

References 17 publications

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“…Although spores are vulnerable to killing by macrophages, and infection has been thought to arise from extracellular spores (32), we found that over 95% of spores were taken up by two hours of incubation, and that spores converted to yeast, which replicated inside alveolar macrophages. Although we are currently unable to monitor spore transition in vivo in real time, our imaging in vitro established intracellular transition and replication inside primary alveolar macrophages.…”

Section: Discussionmentioning

confidence: 72%

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: Discussionmentioning

confidence: 72%

The Unappreciated Intracellular Lifestyle of Blastomyces dermatitidis

Sterkel

Mettelman

Wüthrich

et al. 2015

The Journal of Immunology

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“…This observation echoes reports that dimorphic fungi can manifest morphological changes in response to macrophages. In this regard, Coccidioides immitis arthroconidia grow as spherules and mycelia in the presence and absence of leukocytes, respectively (15); murine macrophages block the dimorphic transition of B. dermatitidis (38); S. schenckii filament in response to macrophages (31); and phagocytosis of H. capsulatum results in the emergence of unusual morphologies, including elongated variants with short mycelial extensions (11). For H. capsulatum, both yeast cells maintained at 37°C and conidia grown at room temperature replicated by using amoebae as the only nutritional source.…”

Section: Discussionmentioning

confidence: 99%

Interaction ofBlastomyces dermatitidis,Sporothrix schenckii, andHistoplasma capsulatumwithAcanthamoeba castellanii

et al. 2004

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Several dimorphic fungi are important human pathogens, but the origin and maintenance of virulence in these organisms is enigmatic, since an interaction with a mammalian host is not a requisite for fungal survival. Recently, Cryptococcus neoformans was shown to interact with macrophages, slime molds, and amoebae in a similar manner, suggesting that fungal pathogenic strategies may arise from environmental interactions with phagocytic microorganisms. In this study, we examined the interactions of three dimorphic fungi with the soil amoeba Acanthameobae castellanii. Yeast forms of Blastomyces dermatitidis, Sporothrix schenckii, and Histoplasma capsulatum were each ingested by amoebae and macrophages, and phagocytosis of yeast cells resulted in amoeba death and fungal growth. H. capsulatum conidia were also cytotoxic to amoebae. For each fungal species, exposure of yeast cells to amoebae resulted in an increase in hyphal cells. Exposure of an avirulent laboratory strain of H. capsulatum to A. castellanii selected for, or induced, a phenotype of H. capsulatum that caused a persistent murine lung infection. These results are consistent with the view that soil amoebae may contribute to the selection and maintenance of certain traits in pathogenic dimorphic fungi that confer on these microbes the capacity for virulence in mammals.

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“…In addition, alveolar macrophages have been shown to inhibit the transformation of conidia to the pathogenic yeast form (113). This is an important step in terms of pathogenesis, because the yeast form, which possesses a thick capsule, is very difficult for phagocytes to ingest and kill.…”

Section: Pathogenesis and Pathologymentioning

confidence: 99%

Clinical and Laboratory Update on Blastomycosis

2010

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SUMMARY Blastomycosis is endemic in regions of North America that border the Great Lakes and the St. Lawrence River, as well as in the Mississippi River and Ohio River basins. Men are affected more often than women and children because men are more likely to participate in activities that put them at risk for exposure to Blastomyces dermatitidis. Human infection occurs when soil containing microfoci of mycelia is disturbed and airborne conidia are inhaled. If natural defenses in the alveoli fail to contain the infection, lymphohematogenous dissemination ensues. Normal host responses generate a characteristic pyogranulomatous reaction. The most common sites of clinical disease are the lung and skin; osseous, genitourinary, and central nervous system manifestations follow in decreasing order of frequency. Blastomycosis is one of the great mimickers in medicine; verrucous cutaneous blastomycosis resembles malignancy, and mass-like lung opacities due to B. dermatitidis often are confused with cancer. Blastomycosis may be clinically indistinguishable from tuberculosis. Diagnosis is based on culture and direct visualization of round, multinucleated yeast forms that produce daughter cells from a single broad-based bud. Although a long course of amphotericin B is usually curative, itraconazole is also highly effective and is the mainstay of therapy for most patients with blastomycosis.

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Macrophage- and Oxidant-Mediated Inhibition of the Ability of Live Blastomyces dermatitidis Conidia to Transform to the Pathogenic Yeast Phase: Implications for the Pathogenesis of Dimorphic Fungal Infections

Cited by 35 publications

References 17 publications

The Unappreciated Intracellular Lifestyle of Blastomyces dermatitidis

The Unappreciated Intracellular Lifestyle of Blastomyces dermatitidis

Interaction ofBlastomyces dermatitidis,Sporothrix schenckii, andHistoplasma capsulatumwithAcanthamoeba castellanii

Clinical and Laboratory Update on Blastomycosis

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