How neutrophils kill fungi

Gazendam, Roel P.; Geer, Annemarie van de; Roos, Dirk; Berg, Timo K. van den; Kuijpers, Taco W.

doi:10.1111/imr.12454

Cited by 123 publications

(110 citation statements)

References 134 publications

(309 reference statements)

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“…In mice, depletion of neutrophils increased susceptibility to cutaneous Candida infections (53) and also increased the risk of lethal invasion following experimental mucosal damage (54). Humans with genetic defects that impair neutrophil functions, such as the autosomal recessive myeloperoxidase deficiency, are at greatly increased risk of systemic Candidiasis, suggesting an important role for neutrophils and other phagocytes (55). Neutrophil extracellular traps (NETs) facilitate killing of C. albicans , although their functional importance against this pathogen is debated (55–57).…”

Section: Innate Immune Responsesmentioning

confidence: 99%

“…Humans with genetic defects that impair neutrophil functions, such as the autosomal recessive myeloperoxidase deficiency, are at greatly increased risk of systemic Candidiasis, suggesting an important role for neutrophils and other phagocytes (55). Neutrophil extracellular traps (NETs) facilitate killing of C. albicans , although their functional importance against this pathogen is debated (55–57). NET formation upon Candida exposure is operational in newborns and, therefore, a neonatal deficiency in NET does not explain their susceptibility to infections (58).…”

Section: Innate Immune Responsesmentioning

confidence: 99%

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Antifungal Immunological Defenses in Newborns

2017

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Newborns are prone to fungal infections, largely due to Candida species. The immunological basis for this vulnerability is not yet fully understood. However, useful insights can be gained from the knowledge of the maturation of immune pathways during ontogeny, particularly when placed in context with how rare genetic mutations in humans predispose to fungal diseases. In this article, we review these most current data on immune functions in human newborns, highlighting pathways most relevant to the response to Candida. While discussing these data, we propose a framework of why deficiencies in these pathways make newborns particularly vulnerable to this opportunistic pathogen.

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Section: Innate Immune Responsesmentioning

confidence: 99%

Section: Innate Immune Responsesmentioning

confidence: 99%

Antifungal Immunological Defenses in Newborns

2017

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“…Neutrophils are critical for elimination of A. fumigatus from the human host (52); however, the exact extracellular mechanisms of how PMNs kill A. fumigatus hyphae are not known (52). A. fumigatus -triggered neutrophil extracellular traps are slightly fungistatic but do not account for the full activity of neutrophils (22, 23).…”

Section: Discussionmentioning

confidence: 99%

Human neutrophils produce antifungal extracellular vesicles againstAspergillus fumigatus

Shopova

Belyaev

Dasari

et al. 2019

Preprint

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AbstractPolymorphonuclear granulocytes (PMNs) are indispensable for controlling life-threatening fungal infections. In addition to various effector mechanisms, PMNs also produce extracellular vesicles (EVs). Their contribution to antifungal defense has remained unexplored. We reveal that the clinically important human pathogenic fungus Aspergillus fumigatus triggers PMNs to release a distinct set of antifungal EVs (afEVs). Proteome analyses indicated that afEVs are enriched in antimicrobial proteins. The cargo and release kinetics of EVs are modulated by the fungal strain confronted. Tracking of afEVs indicated that they associated with fungal cells and even entered fungal hyphae, resulting in alterations in the morphology of the fungal cell wall and dose-dependent antifungal effects. Two human proteins enriched in afEVs, cathepsin G and azurocidin, were heterologously expressed in fungal hyphae, which led to reduced fungal growth relative to a control retinol binding protein 7 producing strain. In conclusion, the production of afEVs by PMNs offers an intriguing, previously overlooked mechanism of antifungal defense against A. fumigatus.ImportanceInvasive fungal infections caused by the mold Aspergillus fumigatus are a growing concern in the clinic due to the increasing use of immunosuppressive therapies and increasing antifungal drug resistance. These infections result in high mortality as treatment and diagnostic options remain limited. In healthy individuals, neutrophilic granulocytes are critical for elimination of A. fumigatus from the host; however, the exact extracellular mechanism of neutrophil-mediated antifungal activity remains unresolved. Here, we present a mode of antifungal defense employed by human neutrophils against A. fumigatus not previously described. We find that extracellular vesicles produced by neutrophils in response to A. fumigatus infection are able to associate with the fungus, limit growth, and elicit cell damage by delivering antifungal cargo. In the end, antifungal extracellular vesicle biology provides a significant step forward in our understanding of A. fumigatus host pathogenesis and opens up novel diagnostic and therapeutic possibilities.

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“…However, although neutrophils activation is usually associated with pathogen containment and elimination, overactivation may be harmful to the host (24,25), so a tight regulatory system for neutrophil activation is important (26). Although neutrophils are known to be important in several fungal infections such as Candida albicans (27), Aspergillus fumigatus. (28), Cryptococcus neoformans (29), Paracoccidioides brasiliensis (30) and Sporothrix schenkii (31), few studies have focused on the neutrophils response during CBM infection.…”

Section: Introductionmentioning

confidence: 99%

Fonsecaea pedrosoiconidia and hyphae activate neutrophils distinctly: Requirement of TLR-2 and TLR-4 in neutrophil effector functions

Breda

Almeida

et al. 2020

Preprint

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Chromoblastomycosis is a chronic and progressive subcutaneous mycosis caused mainly by the fungus Fonsecaea pedrosoi. The infection is characterized by erythaematous papules and the histological sections demonstrating an external layer of fibrous tissue and an internal layer of thick granulomatous inflammatory tissue containing mainly macrophages and neutrophils. Several groups have been studying the roles of the innate and adaptive immune systems in F. pedrosoi infection; however, few studies have focused on the role of neutrophils in this infection. In the current study, we verified the importance of murine neutrophils in the killing of F. pedrosoi conidia and hyphae. We demonstrate that phagocytosis and reactive oxygen species during infection with conidia are TLR-2 and TLR-4-dependent and are essentials for conidial killing. Meanwhile, hyphal killing occurs by NETs formation, in a TLR-2, TLR-4 and ROS-independent manner. In vivo experiments showed that TLR-2 and TLR-4 are also important in Chromoblastomycosis infection. TLR-2KO and TLR-4KO animals had lower levels of MIP-2 and KC chemokines and impaired neutrophil migration to the infected site. These animals also had higher fungal loads during infection with F. pedrosoi conidia, confirming that TLR-2 and TLR-4 are essential receptors for F. pedrosoi recognition and immune system activation. Therefore, this study demonstrated for the first time that neutrophils activation during F. pedrosoi is conidial or hyphal-specific, with TLR-2 and TLR-4 being essential during conidial infection but unnecessary for hyphal killing by neutrophilsAuthor SummaryChromoblastomycosis (CBM) is a chronic and progressive subcutaneous mycosis that affects mainly low-income individuals, such as farm workers. CBM have been diagnosed all over the world, but the majority of cases were diagnosed in tropical and subtropical climate countries. The treatment is difficult and involves the combination of antifungal prescriptions, cryo/heat-therapy and, in some cases, surgery to remove all the infected tissue. The treatment is long (at least 6 months) and expensive, leading to a high rate of treatment dropout and disease relapse. However, the understanding of pathogen-host interaction is far from being elucitaded. Our understanding is that this pathogen-host interaction in CBM needs to be uncovered so a different and more effective treatment could be proposed to help those patients that are struggling against this chronic infection. Therefore, our study shed a light in neutrophils and innate immune response against this fungal infection, showing the neutrophils capacity to kill Fonsecaea pedrosoi conidia and hifa, showing the importance of toll-like receptors 2 and 4 in the neutrophil fungicidal capacity against F. pedrosoi conidia but not hyphae. Therefore this work help to the better understanding of how our organism fights back in the CBM infection.

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How neutrophils kill fungi

Cited by 123 publications

References 134 publications

Antifungal Immunological Defenses in Newborns

Antifungal Immunological Defenses in Newborns

Human neutrophils produce antifungal extracellular vesicles againstAspergillus fumigatus

Fonsecaea pedrosoiconidia and hyphae activate neutrophils distinctly: Requirement of TLR-2 and TLR-4 in neutrophil effector functions

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