Blastomyces dermatitidis Yeast Cells Inhibit Nitric Oxide Production by Alveolar Macrophage Inducible Nitric Oxide Synthase

Rocco, Nicole; Carmen, John C.; Klein, Bruce S.

doi:10.1128/iai.01249-10

Cited by 45 publications

(28 citation statements)

References 37 publications

(34 reference statements)

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“…While our flow cytometric analysis was not sensitive enough to reliably detect leukocyte interactions with <10 4 spores, others have reported that as few as 70 spores are sufficient to cause disease and death in mice (29). While the inoculum of spores that causes disease in humans is unknown, our findings demonstrate that at low inocula most of the infectious spores enter alveolar macrophages, a niche in which they undergo morphogenesis to initiate infection and suppress innate host defense such as NO and TNF-α production (30, 31). …”

Section: Discussionmentioning

confidence: 87%

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: 87%

The Unappreciated Intracellular Lifestyle of Blastomyces dermatitidis

Sterkel

Mettelman

Wüthrich

et al. 2015

The Journal of Immunology

Self Cite

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“…IFN-γ activated macrophages have been shown to have fungicidal activity against Histoplasma capsulatum (84-86) while presence of IL-4 and IL-10 results in inhibition of apoptosis and increase in disease severity (87). M1 activated macrophages have also been associated with antifungal effects against Aspergillus fumigatus (88), Blastomyces dermatitidis (89-91), and Paracoccidioides brasiliensis (90, 92, 93). Therefore, the development of therapeutics that induce M1 macrophage activation via an IFN-γ/STAT1 mechanism may provide protection against a myriad of microbial pathogens.…”

Section: Discussionmentioning

confidence: 99%

STAT1 Signaling Is Essential for Protection against Cryptococcus neoformans Infection in Mice

Wager

Hole

Wozniak

et al. 2014

The Journal of Immunology

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Non-protective immune responses to highly virulent Cryptococcus neoformans strains, such as H99, are associated with Th2-type cytokine production, alternatively activated macrophages and inability of the host to clear the fungus. In contrast, experimental studies show that protective immune responses against cryptococcosis are associated with Th1-type cytokine production and classical macrophage activation. The protective response induced during C. neoformans strain H99γ (C. neoformans strain H99 engineered to produce murine interferon-γ) infection correlates with enhanced phosphorylation of the transcription factor STAT1 in macrophages; however, the role of STAT1 in protective immunity to C. neoformans is unknown. The current studies examined the effect of STAT1-deletion in murine models of protective immunity to C. neoformans. Survival and fungal burden were evaluated in WT and STAT1 KO mice infected with either strain H99γ or C. neoformans strain 52D (unmodified clinical isolate). Both strains H99γ and 52D were rapidly cleared from the lungs, did not disseminate to the CNS, or cause mortality in the WT mice. Conversely, STAT1 KO mice infected with H99γ or 52D had significantly increased pulmonary fungal burden, CNS dissemination, and 90-100% mortality. STAT1-deletion resulted in a shift from Th1 to Th2 cytokine bias, pronounced lung inflammation and defective classical macrophage activation. Pulmonary macrophages from STAT1 KO mice exhibited defects in nitric oxide production correlating with inefficient inhibition of fungal proliferation. These studies demonstrate that STAT1 signaling is essential not only for regulation of immune polarization but for the classical activation of macrophages that occurs during protective anti-cryptococcal immune responses.

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“…Conidia which escape the initial phagocytic response rapidly convert to a yeast form that is more resistant to phagocytosis and killing. In in vitro studies, B. dermatitidis yeast evades macrophage defenses [28] and suppresses nitric oxide production by inhibition of inducible nitric oxide synthase [29]. Several virulence factors have been associated with the pathogenicity of B. dermatitidis.…”

Section: Pathogenesis and Immunologymentioning

confidence: 99%