Killing of
            <i>Aspergillus fumigatus</i>
            by Alveolar Macrophages Is Mediated by Reactive Oxidant Intermediates

Philippe, B.; Ibrahim-Granet, Oumaïma; Prévost, Marie-Claude; Gougerot-Pocidalo, M A; Pérez, María Sánchez; Meeren, Anne Van der; Latgé, Jean‐Paul

doi:10.1128/iai.71.6.3034-3042.2003

Cited by 392 publications

(382 citation statements)

References 37 publications

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“…Our data are consistent with those of a previous study that showed that intracellular conidial swelling is necessary to elicit production ROS by alveolar macrophages (18). In the absence of dectin-1-mediated ROS production, other, potentially less inflammatory, antimicrobial killing mechanisms may play a role in macrophage recognition and killing of inhaled, resting conidia.…”

Section: Discussionsupporting

confidence: 92%

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Dectin-1 and TLRs Permit Macrophages to Distinguish between Different Aspergillus fumigatus Cellular States

Gersuk

Underhill

Zhou

et al. 2006

The Journal of Immunology

316

284

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Aspergillus fumigatus is a common cause of invasive and allergic pulmonary disease. Resting conidia of the filamentous fungus are constantly inhaled, but cause infection only after initiating hyphal growth. In this study, we have explored whether macrophages can distinguish between resting spores and the maturing, potentially invasive form of the fungus. Although macrophages bind and ingest A. fumigatus resting conidia efficiently, there is little inflammatory response; NF-κβ is not activated, inflammatory cytokines are not induced, and reactive oxygen species are not produced. However, maturing A. fumigatus conidia and germ tubes stimulate NF-κβ, secretion of proinflammatory cytokines and production of reactive oxygen by human monocyte-derived macrophages and murine macrophages from multiple anatomical sites. These responses are in part mediated by dectin-1, which binds cell wall β-glucan that is not present on the surface of dormant conidia, but is present after cellular swelling and loss of the hydrophobic proteinaceous cell wall. Dectin-1 binding to germ tubes augments, but is not required for, TLR2-mediated inflammatory cytokine secretion. Dectin-1 recognition of germ tubes also stimulates TNF-α production in the absence of both TLR2 and MyD88 signaling. These data demonstrate one mechanism by which the pulmonary inflammatory response is tailored toward metabolically active cells, thereby avoiding unnecessary tissue damage with frequent inhalation of ubiquitous spores.

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Section: Discussionsupporting

confidence: 92%

“…In addition to inflammatory cytokine production, initial host defense to A. fumigatus involves macrophage production of ROS (18). We examined the relative abilities of resting conidia and germ tubes to induce ROS production by murine bone marrowderived macrophages.…”

Section: A Fumigatus Germ Tubes But Not Conidia Activate Proinflammentioning

confidence: 99%

Dectin-1 and TLRs Permit Macrophages to Distinguish between Different Aspergillus fumigatus Cellular States

Gersuk

Underhill

Zhou

et al. 2006

The Journal of Immunology

316

284

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“…Calcineurin inhibition delayed phagocytosis of SC in hMDMs (P , 0.01) and hAMs (P = 0.04) early postinfection, but phagocytosis of RC was not affected ( Figures 2C, E2B, and E2C). We measured reactive oxygen species (ROS) production and cathepsin B (a lysosomal cysteine protease) activation, which are critical for Af killing (22,23). ROS production was partially calcineurin dependent (P , 0.0001) but had no effect on mitochondrial ROS (Figures 2D, E2D, and E2E) or activated cathepsin B production ( Figures 2E and 2F).…”

Section: Original Articlementioning

confidence: 99%

Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus during Macrophage Cell Death

Shah

Kannambath

Herbst

et al. 2016

Am J Respir Crit Care Med

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Rationale: Pulmonary aspergillosis is a lethal mold infection in the immunocompromised host. Understanding initial control of infection and how this is altered in the immunocompromised host are key goals for comprehension of the pathogenesis of pulmonary aspergillosis.Objectives: To characterize the outcome of human macrophage infection with Aspergillus fumigatus and how this is altered in transplant recipients on calcineurin inhibitor immunosuppressants. Methods:We defined the outcome of human macrophage infection with A. fumigatus, as well as the impact of calcineurin inhibitors, through a combination of single-cell fluorescence imaging, transcriptomics, proteomics, and in vivo studies.Measurements and Main Results: Macrophage phagocytosis of A. fumigatus enabled control of 90% of fungal germination. However, fungal germination in the late phagosome led to macrophage necrosis. During programmed necroptosis, we observed frequent cell-cell transfer of A. fumigatus between macrophages, which assists subsequent control of germination in recipient macrophages. Lateral transfer occurred through actin-dependent exocytosis of the late endosome in a vasodilator-stimulated phosphoprotein envelope. Its relevance to the control of fungal germination was also shown by direct visualization in our zebrafish aspergillosis model in vivo. The calcineurin inhibitor FK506 (tacrolimus) reduced cell death and lateral transfer in vitro by 50%. This resulted in uncontrolled fungal germination in macrophages and also resulted in hyphal escape.Conclusions: These observations identify programmed, necrosisdependent lateral transfer of A. fumigatus between macrophages as an important host strategy for controlling fungal germination. This process is critically dependent on calcineurin. Our studies provide fundamental insights into the pathogenesis of pulmonary aspergillosis in the immunocompromised host.

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“…In COPD patients ciliary activity impairment, immunosuppression due to alveolar macrophage and neutrophil inhibition in those treated with steroids and also receiving broad-spectrum antibiotics, play an important role in the development of IPA [54] . The most common invasive aspergillosis-associated underlying disease in ICUs is COPD, followed by SOT [53] .…”

Section: Airway Invasive Aspergillosis Is An Uncommon Invasive Diseasmentioning

confidence: 99%

An update of clinical characteristics and imaging findings of pulmonary aspergillosis

Sah

Liu

Ganganah

et al. 2015

IJDI

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Pulmonary aspergillosis (PA) is a clinical spectrum of rapidly progressive potentially fatal opportunistic mycosis usually caused by Aspergillus organisms. In the recent years, the number of patients with invasive pulmonary aspergillosis (IPA) has increased and it remains a major cause of morbidity and mortality in immunocompromised patients. Chest CT plays an important role in the early diagnosis of IPA and should be included in the investigative protocol. Typical imaging findings of IPA include nodule, consolidation, the halo sign, the hypodense sign and the air crescent sign. CT Angiography (CTA) has a higher sensitivity for detecting angioinvasive aspergillosis. However, the diagnosis of pulmonary aspergillosis remains challenging radiologically in immunocompetent chronic obstructive pulmonary disease (COPD) and critically ill patients in intensive care unit (ICU) because of the non-specific CT findings and further studies are needed to establish the confirm diagnosis.

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

Cited by 392 publications

References 37 publications

Dectin-1 and TLRs Permit Macrophages to Distinguish between Different Aspergillus fumigatus Cellular States

Dectin-1 and TLRs Permit Macrophages to Distinguish between Different Aspergillus fumigatus Cellular States

Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus during Macrophage Cell Death

An update of clinical characteristics and imaging findings of pulmonary aspergillosis

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