Fungal antioxidant pathways promote survival against neutrophils during infection

Leal, Sixto M.; Vareechon, Chairut; Cowden, Susan; Cobb, Brian A.; Latgé, Jean Paul; Momany, Michelle; Pearlman, Eric

doi:10.1172/jci63239

Cited by 121 publications

(169 citation statements)

References 78 publications

(116 reference statements)

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“…TLR4 is responsible for neutrophil phagocytosis and the subsequent killing of conidia, while the CD18 subunit of CR3 is responsible for the production of ROS upon contact with hyphae, and it induces hyphal killing by neutrophils in the absence of active complement [8,11,34,35]. TLR2 could play a minor role in the killing of conidia, although the in vivo data does not support any significant role for TLR2 in anti- Aspergillus immunity [34,35].…”

Section: Discussionmentioning

confidence: 99%

“…TLR2 could play a minor role in the killing of conidia, although the in vivo data does not support any significant role for TLR2 in anti- Aspergillus immunity [34,35]. Dectin-1 detects β-glucans in the fungal cell wall and is important for ROS production and killing by neutrophils of unopsonized swollen conidia [36], but play no role/a minor role in neutrophil oxidase activity and killing after engagement with unopsonized hyphae [8,11]. Although fungal immune recognition by neutrophils is dependent on multiple receptors, we did not observe residual phagocytosis of the different Aspergillus morphotypes in the absence of serum in our experimental setup.…”

Section: Discussionmentioning

confidence: 99%

“…A qualitative or quantitative defect in the neutrophils is one of the most important predisposing factors for invasive aspergillosis [4,5,6]. Killing of A. fumigatus by neutrophils is mediated by the production of reactive oxygen species (ROS) and the release of the neutrophil granular content [7,8,9,10]. Patients with chronic granulomatous disease, a genetic lesion causing defective production of ROS, have an increased risk for the development of invasive fungal infections, particularly invasive aspergillosis [4].…”

Section: Introductionmentioning

confidence: 99%

“…CD11b/CD18) or dectin-1 or indirect via opsonization [8,11,12]. In general, for efficient clearance by neutrophils, microbes need to be opsonized by humoral factors to establish effective phagocytosis and intracellular killing.…”

Section: Introductionmentioning

confidence: 99%

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Effective Neutrophil Phagocytosis of Aspergillus fumigatus Is Mediated by Classical Pathway Complement Activation

et al. 2015

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Aspergillus fumigatus is an important airborne fungal pathogen and a major cause of invasive fungal infections. Susceptible individuals become infected via the inhalation of dormant conidia. If the immune system fails to clear these conidia, they will swell, germinate and grow into large hyphal structures. Neutrophils are essential effector cells for controlling A. fumigatus infection. In general, opsonization of microbial particles is crucial for efficient phagocytosis and killing by neutrophils. Although the antibodies present in human serum do bind to all fungal morphotypes, we observed no direct antibody-mediated phagocytosis of A. fumigatus. We show that opsonization, phagocytosis and killing by neutrophils of A. fumigatus is complement-dependent. Using human sera depleted of key complement components, we investigated the contribution of the different complement initiation pathways in complement activation on the fungal surface. We describe the classical complement pathway as the main initiator of complement activation on A. fumigatus swollen conidia and germ tubes. Antibodies play an important role in complement activation and efficient innate recognition, phagocytosis and killing of A. fumigatus by neutrophils.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effective Neutrophil Phagocytosis of Aspergillus fumigatus Is Mediated by Classical Pathway Complement Activation

et al. 2015

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“…Moreover, one of the most disposing risk factors for invasive aspergillosis is a depletion and/or functional impairment of neutrophils (6)(7)(8). Killing of Aspergillus fumigatus by neutrophils is mediated by the release of reactive oxygen species and neutrophil granular content (9)(10)(11)(12).…”

mentioning

confidence: 99%

High Intracellular Concentrations of Posaconazole Do Not Impact on Functional Capacities of Human Polymorphonuclear Neutrophils and Monocyte-Derived Macrophages In Vitro

Farowski

Cornely

Hartmann

2016

Antimicrob Agents Chemother

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Posaconazole is a commonly used antifungal for the prophylaxis and treatment of invasive fungal infections. We previously demonstrated that the intracellular concentration of posaconazole in peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) was greatly increased compared to the plasma concentration. As these professional phagocytes are crucial to combat fungal infections, we set out to investigate if and how, beneficial or deleterious, this high loading of intracellular posaconazole impacts the functional capacities of these cells. Here, we show that high intracellular concentrations of posaconazole do not significantly impact PMN and monocyte-derived macrophage function in vitro. In particular, killing capacity and cytoskeletal features of PMN, such as migration, are not affected, indicating that these cells serve as vehicles for posaconazole to the site of infection. Moreover, since posaconazole as such slowed the germination of Aspergillus fumigatus conidia, infected neutrophils released less reactive oxygen species (ROS). Based on these findings, we propose that the delivery of posaconazole by neutrophils to the site of Aspergillus species infection warrants control of the pathogen and preservation of tissue integrity at the same time. Posaconazole is a broad-spectrum triazole antifungal approved for prophylaxis and treatment of opportunistic invasive fungal infections (IFI) in immunocompromised patients. The majority of all IFI (probably more than 95%) are attributable to Aspergillus spp. and Candida spp. (1, 2). Aspergillus spp. are ubiquitous soil-dwelling fungi, often found in walls and dust. Due to their small size (2-to 4-m diameter), Aspergillus conidia (spores) tend to remain airborne. It is estimated that all humans inhale at least several hundred Aspergillus fumigatus conidia per day (3). Upon inhalation, these conidia may germinate at body temperature in the terminal airways and alveoli, causing invasive pulmonary aspergillosis (3). Alveolar macrophages constitute the first line of defense against invading conidia. They immediately phagocytize conidia, thereby restricting their initial spread into the alveoli. The process of phagocytosis is accompanied by secretion of proinflammatory cytokines, leading to autocrine activation of the macrophage and attraction of other immune cells to the site of infection (4). It has been shown that recruitment of neutrophils is essential for efficient clearing of Aspergillus fumigatus conidia (5). Moreover, one of the most disposing risk factors for invasive aspergillosis is a depletion and/or functional impairment of neutrophils (6-8). Killing of Aspergillus fumigatus by neutrophils is mediated by the release of reactive oxygen species and neutrophil granular content (9-12).Therapeutic substances are differentially distributed to various compartments of the human body, which impacts their pharmacokinetics and pharmacodynamics. With regard to the question of whether cells of the peripheral blood constitute a relevant compartment f...

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Aspergillus fumigatus corneal infection is regulated by chitin synthases and by neutrophil–derived acidic mammalian chitinase

et al. 2019

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Aspergillus fumigatus is an important cause of pulmonary and systemic infections in immune compromised individuals, and of corneal ulcers and blindness in immune competent patients. To examine the role of chitin synthases inAspergillus corneal infection, we analyzed Aspergillus mutants of chitin synthase family 1 and family 2, and found that compared with the parent strain, the quadruple mutants from both families were more readily killed by neutrophils in vitro, and that both also exhibited impaired hyphal growth in the cornea. Further, inhibition of chitin synthases using Nikkomycin Z enhanced neutrophil killing in vitro and in vivo in a murine model of A. fumigatus corneal infection. Acidic mammalian chitinase (AMCase) is mostly produced by macrophages in asthmatic lungs; however, we now demonstrate that neutrophils are a major source of AMCase, which inhibits hyphal growth. In A. fumigatus corneal infection, neutrophils are the major source of AMCase, and addition of AMCase inhibitors or adoptive transfer of neutrophils from AMCase −/− mice resulted in impaired hyphal killing. Together, these findings identify chitin synthases as important fungal virulence factors and neutrophilderived AMCase as an essential mediator of host defense.Keywords: Acidic mammalian chitinase r Aspergillus fumigatus r Corneal infection r Chitin synthase r Keratitis r Neutrophil Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Fungal antioxidant pathways promote survival against neutrophils during infection

Cited by 121 publications

References 78 publications

Effective Neutrophil Phagocytosis of <b><i>Aspergillus</i></b> <b><i>fumigatus</i></b> Is Mediated by Classical Pathway Complement Activation

Effective Neutrophil Phagocytosis of <b><i>Aspergillus</i></b> <b><i>fumigatus</i></b> Is Mediated by Classical Pathway Complement Activation

High Intracellular Concentrations of Posaconazole Do Not Impact on Functional Capacities of Human Polymorphonuclear Neutrophils and Monocyte-Derived Macrophages In Vitro

Aspergillus fumigatus corneal infection is regulated by chitin synthases and by neutrophil–derived acidic mammalian chitinase

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