Suppression of Aspergillus fumigatus Germination by Neutrophils Is Enhanced by Endothelial-Derived CSF3 Production

Zhang, Wenxin; He, Dan; Wei, Yizhen; Shang, Shumi; Liu, Dong; Wang, Li

doi:10.3389/fmicb.2022.837776

Cited by 3 publications

(4 citation statements)

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“…The changes in some chemokines’ trends ( Figure 3 ) and increased proportion of neutrophils in infected G2A -/- mice ( Figure 4B ) suggested a prominent role of neutrophils in enhancing the survival of G2A -/- mice. Thus, we asked if granulocyte cell stimulating factor (G-CSF) levels could be altered in infected G2A -/- mice in comparison to G2A +/+ as G-CSF is important for neutrophil survival, proliferation, and differentiation ( 44 , 45 ) and was recently shown to be involved in the suppression of A. fumigatus germination ( 45 ). It is also involved in damaging hyphae of A. fumigatus by enhancing the neutrophil oxidative burst ( 46 ).…”

Section: Resultsmentioning

confidence: 99%

“…In mouse infections, G-CSF administration has been overall effective in protecting non-neutropenic mice from invasive candidiasis and is effective for mice with less severe neutropenia infected with A. fumigatus ( 46 ). Recent work has shown that G-CSF enhances the suppression of A. fumigatus germination ( 45 ). Our work shows that G2A may dampen neutrophilic recruitment during initial inflammation with A. fumigatus.…”

Section: Discussionmentioning

confidence: 99%

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Loss of the mammalian G-protein coupled receptor, G2A, modulates severity of invasive pulmonary aspergillosis

et al. 2023

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BackgroundAspergillus fumigatus is a well-known opportunistic pathogen that causes a range of diseases including the often-fatal disease, invasive pulmonary aspergillosis (IPA), in immunocompromised populations. The severity of IPA is dependent on both host- and pathogen-derived signaling molecules that mediate host immunity and fungal growth. Oxylipins are bioactive oxygenated fatty acids known to influence host immune response and Aspergillus developmental programs. Aspergillus synthesizes 8-HODE and 5,8-diHODE that have structural similarities to 9-HODE and 13-HODE, which are known ligands of the host G-protein-coupled receptor G2A (GPR132).Materials and methodsOxylipins were extracted from infected lung tissue to assess fungal oxylipin production and the Pathhunter β-arrestin assay was used to assess agonist and antagonist activity by fungal oxylipins on G2A. An immunocompetent model of A. fumigatus infection was used to assess changes in survival and immune responses for G2A-/- mice.ResultsHere we report that Aspergillus oxylipins are produced in lung tissue of infected mice and in vitro ligand assays suggest 8-HODE is a G2A agonist and 5,8-diHODE is a partial antagonist. To address the hypothesis that G2A could be involved in the progression of IPA, we assessed the response of G2A-/- mice to A. fumigatus infection. G2A-/- mice showed a survival advantage over wild-type mice; this was accompanied by increased recruitment of G2A-/- neutrophils and increased levels of inflammatory markers in A. fumigatus-infected lungs.ConclusionsWe conclude that G2A suppresses host inflammatory responses to Aspergillus fumigatus although it remains unclear if fungal oxylipins are involved in G2A activities.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Loss of the mammalian G-protein coupled receptor, G2A, modulates severity of invasive pulmonary aspergillosis

et al. 2023

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“…Murine neutrophils also phagocytose and kill Aspergillus conidia via Dectin-1 and CARD-9 depending on Syk-kinase signaling and downstream NADPH oxidase-induced ROS production [56]. In addition, neutrophils release antimicrobial peptides, proteases, and neutrophil extracellular traps (NET) to avoid fungal invasion [57]. The ROS also mediates release of neutrophil extracellular traps (NETs) [58].…”

Section: Fungal Pulmonary Diseasesmentioning

confidence: 99%

Could the Lung Be a Gateway for Amphotericin B to Attack the Army of Fungi?

Patricio

Pereira²,

Sarcinelli

et al. 2022

Pharmaceutics

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Fungal diseases are a significant cause of morbidity and mortality worldwide, primarily affecting immunocompromised patients. Aspergillus, Pneumocystis, and Cryptococcus are opportunistic fungi and may cause severe lung disease. They can develop mechanisms to evade the host immune system and colonize or cause lung disease. Current fungal infection treatments constitute a few classes of antifungal drugs with significant fungi resistance development. Amphotericin B (AmB) has a broad-spectrum antifungal effect with a low incidence of resistance. However, AmB is a highly lipophilic antifungal with low solubility and permeability and is unstable in light, heat, and oxygen. Due to the difficulty of achieving adequate concentrations of AmB in the lung by intravenous administration and seeking to minimize adverse effects, nebulized AmB has been used. The pulmonary pathway has advantages such as its rapid onset of action, low metabolic activity at the site of action, ability to avoid first-pass hepatic metabolism, lower risk of adverse effects, and thin thickness of the alveolar epithelium. This paper presented different strategies for pulmonary AmB delivery, detailing the potential of nanoformulation and hoping to foster research in the field. Our finds indicate that despite an optimistic scenario for the pulmonary formulation of AmB based on the encouraging results discussed here, there is still no product registration on the FDA nor any clinical trial undergoing ClinicalTrial.gov.

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“…However, in immunocompromised patients, lung epithelial cells have a reduced ability to clear spores, leading to increased adhesion and germination of A. fumigatus ( 6 ). Some studies have shown that A. fumigatus infects lung epithelial cells in vitro , first adhering to the cell surface, followed by internalization into the cell, and after 6 h of infection, its spores begin to germinate budding tubes, known as small hyphae, which in turn cause an invasive infection and recruit professional phagocytes such as macrophages and neutrophils to the site of infection ( 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

TRAF3 gene regulates macrophage migration and activation by lung epithelial cells infected with Aspergillus fumigatus

Shang,

He,

Liu

et al. 2024

Microbiol Spectr

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Aspergillus fumigatus is an opportunistic pathogen that infects immunocompromised patients and imposes a heavy burden on global health. Searching for key genes in host resistance to A. fumigatus infection can help us understand the mechanisms of A. fumigatus -host interactions and provide new targets for the treatment of fungal infections. TRAF3 is one of the intracellular adapter proteins of the innate immune response that regulates signaling in various cellular processes, including host defense against pathogens. However, the defense mechanism of TRAF3 against A. fumigatus infection remains unknown. In this study, we found that TRAF3 overexpression led to the adhesion and internalization of more spores of A. fumigatus in lung epithelial cells and thus greater host immune surveillance evasion. Meanwhile, TRAF3 was able to regulate the expression of pro-inflammatory cytokines in lung epithelial cells infected with A. fumigatus through the negative regulation of NF-κB and MAPK signaling pathways. In this study, we also examined the effects of TRAF3 in the interaction between lung epithelial cells, macrophages, and A. fumigatus spores, and the results showed that TRAF3-overexpressing lung epithelial cells reduced the migration and activation of macrophages after A. fumigatus infection. In vivo experiments using TRAF3-overexpressing transgenic zebrafish larvae revealed that TRAF3 overexpression increased the fungal load and mortality of zebrafish infected with A. fumigatus . In conclusion, the TRAF3 gene can negatively regulate the resistance of lung epithelial cells to A. fumigatus , which plays an important role in the early infection processes of A. fumigatus . IMPORTANCE Aspergillus fumigatus can infect immunocompromised individuals and cause chronic and fatal invasive fungal infections. A better understanding of the molecular mechanisms of A. fumigatus -host interactions may provide new references for disease treatment. In this study, we demonstrated that the TRAF3 gene plays an important role in the early infection of A. fumigatus by regulating the resistance of lung epithelial cells to A. fumigatus . Macrophages are the most abundant innate immune cells in the alveoli; however, few studies have reported on the interactions between lung epithelial cells and macrophages in response to A. fumigatus invasion. In our study, it was demonstrated that the TRAF3 gene reduces migration to macrophages and cytokine production by negatively regulating lung epithelial cell adhesion and internalization of A. fumigatus spores. Together, our results provide new insights into lung epithelial cell-macrophage interactions during A. fumigatus infection.

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Suppression of Aspergillus fumigatus Germination by Neutrophils Is Enhanced by Endothelial-Derived CSF3 Production

Cited by 3 publications

References 47 publications

Loss of the mammalian G-protein coupled receptor, G2A, modulates severity of invasive pulmonary aspergillosis

Loss of the mammalian G-protein coupled receptor, G2A, modulates severity of invasive pulmonary aspergillosis

Could the Lung Be a Gateway for Amphotericin B to Attack the Army of Fungi?

TRAF3 gene regulates macrophage migration and activation by lung epithelial cells infected with Aspergillus fumigatus

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