Oxidative burst and neutrophil elastase contribute to clearance of Aspergillus fumigatus pneumonia in mice

Prüfer, Steve; Weber, Michael; Stein, Pamela; Bosmann, Markus; Stassen, Michael; Kreft, Andreas; Schild, Hansjörg; Radsak, Markus P.

doi:10.1016/j.imbio.2013.08.010

Cited by 31 publications

(50 citation statements)

References 51 publications

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“…Therefore, inhibition of NE, to decrease airway inflammation and to prevent infections in cystic fibrosis, is currently under investigation. However, in healthy subjects the inhibition of NE favours bacterial, fungal and parasite infections [23,24]. A study conducted in HIV-positive patients, undergoing highly active antiretroviral therapy, containing a protease inhibitor (saquinavir, ritonavir, lopinavir, amprenavir or nelfinavir), showed a significant decrease in neutrophil function [25], which may suggest protease inhibitors might not only affect viral proteases but might also impair the function of neutrophil serine proteases.…”

Section: Discussionmentioning

confidence: 99%

The addition of a protease inhibitor increases the risk of infections in patients with hepatitis C-related cirrhosis

Londoño

Perelló

Cabezas

et al. 2015

Journal of Hepatology

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Section: Discussionmentioning

confidence: 99%

The addition of a protease inhibitor increases the risk of infections in patients with hepatitis C-related cirrhosis

Londoño

Perelló

Cabezas

et al. 2015

Journal of Hepatology

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“…Alveolar macrophages are able to clear conidia by phagocytosis to prevent spore germination (Philippe et al, 2003). Conidia that escape effector functions of alveolar macrophages develop into germtubes and hyphae, whereby effective killing and control require neutrophils (Prufer et al, 2014). A number of fungal components within A. fumigatus serve as ligands for a family of innate immune receptors known as pattern-recognition receptors.…”

Section: Introductionmentioning

confidence: 99%

Concerted Activation of the AIM2 and NLRP3 Inflammasomes Orchestrates Host Protection against Aspergillus Infection

Karki

Man

Malireddi

et al. 2015

Cell Host & Microbe

237

254

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SUMMARY Invasive pulmonary aspergillosis is a leading cause of infection-associated mortality in immunocompromised individuals. Aspergillus fumigatus infection produces ligands that could activate inflammasomes but the contribution of these host defenses remains unclear. We show that two inflammasome receptors, AIM2 and NLRP3, recognize intracellular A. fumigatus and collectively induce protective immune responses. Mice lacking both AIM2 and NLRP3 fail to confine Aspergillus hyphae to inflammatory foci, leading to widespread hyphal dissemination to lung blood vessels. These mice succumb to infection more rapidly than WT mice or mice lacking a single inflammasome receptor. AIM2 and NLRP3 activation initiates assembly of a single cytoplasmic inflammasome platform, composed of the adaptor protein ASC along with caspase-1 and caspase-8. Combined actions of caspase-1 and caspase-8 lead to processing of proinflammatory cytokines IL-1β and IL-18 that critically control the infection. Thus, AIM2 and NLRP3 form a dual cytoplasmic surveillance system that orchestrates responses against A. fumigatus infection.

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“…Apart from oxidase-dependent killing, one of the nonoxidase defense mechanisms, that is, the degranulation and release of elastase, was found in mice to be important in the elimination of A. fumigatus (27). The lactoferrin present in the specific granules of neutrophils has been shown to mediate iron depletion and thus restrict fungal growth as well (28).…”

mentioning

confidence: 99%

Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte Defects

Gazendam

Hamme

Tool

et al. 2016

The Journal of Immunology

162

158

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Neutrophils are known to play a pivotal role in the host defense against Aspergillus infections. This is illustrated by the prevalence of Aspergillus infections in patients with neutropenia or phagocyte functional defects, such as chronic granulomatous disease. However, the mechanisms by which human neutrophils recognize and kill Aspergillus are poorly understood. In this work, we have studied in detail which neutrophil functions, including neutrophil extracellular trap (NET) formation, are involved in the killing of Aspergillus fumigatus conidia and hyphae, using neutrophils from patients with well-defined genetic immunodeficiencies. Recognition of conidia involves integrin CD11b/CD18 (and not dectin-1), which triggers a PI3K-dependent nonoxidative intracellular mechanism of killing. When the conidia escape from early killing and germinate, the extracellular destruction of the Aspergillus hyphae needs opsonization by Abs and involves predominantly recognition via Fcγ receptors, signaling via Syk, PI3K, and protein kinase C to trigger the production of toxic reactive oxygen metabolites by the NADPH oxidase and myeloperoxidase. A. fumigatus induces NET formation; however, NETs did not contribute to A. fumigatus killing. Thus, our findings reveal distinct killing mechanisms of Aspergillus conidia and hyphae by human neutrophils, leading to a comprehensive insight in the innate antifungal response.

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Oxidative burst and neutrophil elastase contribute to clearance of Aspergillus fumigatus pneumonia in mice

Cited by 31 publications

References 51 publications

The addition of a protease inhibitor increases the risk of infections in patients with hepatitis C-related cirrhosis

The addition of a protease inhibitor increases the risk of infections in patients with hepatitis C-related cirrhosis

Concerted Activation of the AIM2 and NLRP3 Inflammasomes Orchestrates Host Protection against Aspergillus Infection

Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte Defects

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