Reaction of Human Alveolar Macrophages to Exposure toAspergillus fumigatusand Inert Particles

Nessa, Khairun; Palmberg, Lena; Johard, Urban; Malmberg, Per; Jarstrand, Connie; Camner, Per

doi:10.1006/enrs.1997.3788

Cited by 18 publications

(15 citation statements)

References 30 publications

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“…Our results were similar to several other comparative studies of fungi such as Aspergillus fumigatus, Saccharomyces cerevisiae, and Candida albicans with inert particles (10,18). The intracellular pH of these fungi-containing phagosomes also increases by 3 h. However, except for S. cerevisiae, the pH reacidifies by 24 h. This decrease in pH at later time points probably reflects intracellular growth of the pathogenic fungi and therefore accumulation of metabolic waste.…”

Section: Discussionsupporting

confidence: 90%

Replication ofCryptococcus neoformansin macrophages is accompanied by phagosomal permeabilization and accumulation of vesicles containing polysaccharide in the cytoplasm

Tucker

Casadevall

2002

Proc. Natl. Acad. Sci. U.S.A.

284

266

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Cryptococcus neoformans (CN), an encapsulated, ubiquitous environmental yeast, is pathogenic for humans, primarily those with compromised immune function. CN is believed to be a facultative intracellular pathogen. Time-lapsed video microscopy revealed that yeast began to replicate and divide 2 hours after ingestion by J774.16 macrophage cells, with the average cell hosting 10 -40 organisms of varying morphologies before ultimately lysing and releasing organisms, either singly or in clumps. Intracellular growth was accompanied by the accumulation of polysaccharide-filled vesicles in the macrophage. Studies with fluorescently labeled dextran revealed that the phagolysosomal compartment became leaky during the course of intracellular infection. Consistent with this observation, phagosomes containing CN had an increased pH relative to similar phagosomes containing inert magnetic beads, as indicated by a colorimetric change in the pH-sensitive Lysosensor dye. Immunocytochemistry revealed differences in the reactivity of polysaccharide elaborated by CN inside macrophages relative to that expressed in vitro. Taken together these results are suggestive of a novel mechanism of intracellular survival by an encapsulated organism, whereby ingestion is followed by damage to the phagosomal membrane resulting in continuity with the cytoplasm, accumulation of polysaccharide-containing vesicles, and possibly, production of a structurally different polysaccharide. Cryptococcus neoformans (CN) is the causative agent of cryptococcosis, a disease that predominantly afflicts immunocompromised hosts but that can occur in healthy individuals as well (reviewed in ref. 1). This yeast is ubiquitous in the environment and is acquired through inhalation of desiccated particles. Infection may be accompanied by dissemination and clinical disease that usually manifests itself as meningitis. The available antifungal therapy is often inadequate for eradicating the infection in individuals with impaired immune function. With the AIDS epidemic and advances in organ transplant technology, there has been an ever increasing population of individuals with compromised immunity, resulting in a large pool of susceptible individuals.CN is unique among the pathogenic fungi in that it has a polysaccharide capsule that is required for virulence. The capsule is antiphagocytic under in vitro conditions without opsonins and immunosuppressive in vivo. The role of the capsule in promoting virulence is complex and includes immunosuppressive effects resulting from shed polysaccharides (reviewed in ref. 1). After ingestion, CN elaborates its capsule, resulting in larger phagosomes. This action potentially serves to dilute lysosomal contents and it provides a physical separation between the surfaces of the yeast cell and the phagosomal membrane where microbicidal compounds are released. However, electron microscopic studies of infected tissue suggest that the capsule may actively function as an intracellular aggressin. CN sheds its polysaccharide in the intracellular...

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Section: Discussionsupporting

confidence: 90%

Replication ofCryptococcus neoformansin macrophages is accompanied by phagosomal permeabilization and accumulation of vesicles containing polysaccharide in the cytoplasm

Tucker

Casadevall

2002

Proc. Natl. Acad. Sci. U.S.A.

284

266

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“…Similar rates of engulfment have been reported for human and rabbit macrophages derived from monocytes (25,26,31). In contrast to the situation for most bacterial pathogens, viable A. fumigatus organisms are not essential for efficient engulfment, as evidenced by the fact that the same phagocytic index scores were calculated whether p-FA-fixed conidia or viable resting conidia were used (10).…”

Section: Discussionsupporting

confidence: 57%

Killing of Aspergillus fumigatus by Alveolar Macrophages Is Mediated by Reactive Oxidant Intermediates

Philippe¹,

Ibrahim-Granet²,

et al. 2003

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Phagocytosis and mechanisms of killing of Aspergillus fumigatus conidia by murine alveolar macrophages (AM), which are the main phagocytic cells of the innate immunity of the lung, were investigated. Engulfment of conidia by murine AM lasts 2 h. Killing of A. fumigatus conidia by AM begins after 6 h of phagocytosis. Swelling of the conidia inside the AM is a prerequisite for killing of conidia. The contributions of NADPH oxidase and inducible nitric oxide synthase to the conidicidal activity of AM were studied using AM from OF1, wild-type and congenic p47phox ؊/؊ 129Sv, and wild-type and congenic iNOS ؊/؊ C57BL/6 mice. AM from p47phox ؊/؊ mice were unable to kill A. fumigatus conidia. Inhibitors of NADPH oxidase that decreased the production of reactive oxidant intermediates inhibited the killing of A. fumigatus without altering the phagocytosis rate. In contrast to NADPH oxidase, nitric oxide synthase does not play a role in killing of conidia. Corticosteroids did not alter the internalization of conidia by AM but did inhibit the production of reactive oxidant intermediates and the killing of A. fumigatus conidia by AM. Impairment of production of reactive oxidant intermediates by corticosteroids is responsible for the development of invasive aspergillosis in immunosuppressed mice.

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“…The primary lung defense against A. fumigatus conidia is mediated by the alveolar macrophage which has been shown to engulf and kill A. fumigatus conidia before these spores have a chance to germinate in the lung (35). Recruited platelets and neutrophils also contribute to fungal killing (5).…”

Section: Discussionmentioning

confidence: 99%

Antifungal and Airway Remodeling Roles for Murine Monocyte Chemoattractant Protein-1/CCL2 During Pulmonary Exposure toAsperigillus fumigatusConidia

Blease¹,

Mehrad

Lukacs³

et al. 2001

The Journal of Immunology

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Asperigillus fumigatus spores or conidia are quickly eliminated from the airways of nonsensitized individuals but persist in individuals with allergic pulmonary responsiveness to fungus. A. fumigatus-induced allergic airway disease is characterized by persistent airway hyperreactivity, inflammation, and fibrosis. The present study explored the role of CCR2 ligands in the murine airway response to A. fumigatus conidia. Nonsensitized and A. fumigatus-sensitized CBA/J mice received an intratracheal challenge of A. fumigatus conidia, and pulmonary changes were analyzed at various times after conidia. Whole lung levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), but neither MCP-3/CCL7 nor MCP-5/CCL12, were significantly elevated at days 3 and 7 after conidia in nonsensitized mice. MCP-1/CCL2 was significantly increased in lung samples from A. fumigatus-sensitized mice at days 14 and 30 after a conidia challenge. Administration of anti-MCP-1/CCL2 antiserum to nonsensitized mice for14 days after the conidia challenge attenuated the clearance of conidia and significantly increased airway hyperreactivity, eosinophilia, and peribronchial fibrosis compared with nonsensitized mice that received conidia and normal serum. Adenovirus-directed overexpression of MCP-1/CCL2 in A. fumigatus-sensitized mice markedly reduced the number of conidia, airway inflammation, and airway hyperresponsiveness at day 7 after the conidia challenge in these mice. Immunoneutralization of MCP-1/CCL2 levels in A. fumigatus-sensitized mice during days14–30 after the conidia challenge did not affect the conidia burden but significantly reduced airway hyperreactivity, lung IL-4 levels, and lymphocyte recruitment into the airways compared with the control group. These data suggest that MCP-1/CCL2 participates in the pulmonary antifungal and allergic responses to A. fumigatus conidia.

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Reaction of Human Alveolar Macrophages to Exposure toAspergillus fumigatusand Inert Particles

Cited by 18 publications

References 30 publications

Replication ofCryptococcus neoformansin macrophages is accompanied by phagosomal permeabilization and accumulation of vesicles containing polysaccharide in the cytoplasm

Replication ofCryptococcus neoformansin macrophages is accompanied by phagosomal permeabilization and accumulation of vesicles containing polysaccharide in the cytoplasm

Killing of Aspergillus fumigatus by Alveolar Macrophages Is Mediated by Reactive Oxidant Intermediates

Antifungal and Airway Remodeling Roles for Murine Monocyte Chemoattractant Protein-1/CCL2 During Pulmonary Exposure toAsperigillus fumigatusConidia

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