Antifungal Drugs Influence Neutrophil Effector Functions

Ries, Frederic; Alflen, Astrid; Lopez, Pamela Aranda; Beckert, Hendrik; Theobald, Matthias; Schild, Hansjörg; Teschner, Daniel; Radsak, Markus P.

doi:10.1128/aac.02409-18

Cited by 9 publications

(10 citation statements)

References 72 publications

(80 reference statements)

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“…drugs work in live, infected animals. All of these drugs are primarily tested and studied in vitro, but the presence of immune cells and the complexity of whole tissues and organs has major effects on drug delivery and efficacy in infected patients (12,13).…”

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confidence: 99%

Efficacy of Voriconazole against Aspergillus fumigatus Infection Depends on Host Immune Function

Rosowski

Huisken

et al. 2020

Antimicrob Agents Chemother

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Antifungal therapy can fail in a remarkable number of patients with invasive fungal disease, resulting in significant morbidity worldwide. A major contributor to this failure is that while these drugs have high potency in vitro, we do not fully understand how they work inside infected hosts. Here, we used a transparent larval zebrafish model of Aspergillus fumigatus infection amenable to real-time imaging of invasive disease as an in vivo intermediate vertebrate model to investigate the efficacy and mechanism of the antifungal drug voriconazole. We found that the ability of voriconazole to protect against A. fumigatus infection depends on host innate immune cells and, specifically, on the presence of macrophages. While voriconazole inhibits fungal spore germination and growth in vitro, it does not do so in larval zebrafish. Instead, live imaging of whole, intact larvae over a multiday course of infection revealed that macrophages slow down initial fungal growth, allowing voriconazole time to target and kill A. fumigatus hyphae postgermination. These findings shed light on how antifungal drugs such as voriconazole may synergize with the immune response in living hosts.

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confidence: 99%

Efficacy of Voriconazole against Aspergillus fumigatus Infection Depends on Host Immune Function

Rosowski

Huisken

et al. 2020

Antimicrob Agents Chemother

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“…Among the mechanisms underlying antifungal agents and macrophages, ROS induction plays important roles (Erwig and Gow, 2016; Thangamani et al, 2017; Ries et al, 2019). Since Ala could induce ROS production in various kinds of tumor cells (Khan et al, 2012; Khan et al, 2013), so we speculated that ROS may be closely associated with the antifungal activity of Ala. As expected, Ala could significantly increase the production of ROS, consistent with our previous reports on Ala and other ROS-inducing antifungal agents (Khan et al, 2012; Khan et al, 2013; Thangamani et al, 2017; Yang et al, 2018a; Ries et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Antifungal effects of alantolactone onCandida albicans:anin vitrostudy

Liu

Zhao

et al. 2021

Preprint

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The human fungal pathogen Candida albicans can cause many kinds of infections, including biofilm infections on medical devices, while the available antifungal drugs are limited to only a few. In this study, alantolactone (Ala) demonstrated antifungal activities against C. albicans, as well as other Candida species, with a MIC of 72 μg/mL. Ala could also inhibit the adhesion, yeast-to-hyphal transition, biofilm formation and development of C. albicans. The exopolysaccharide of biofilm matrix and extracellular phospholipase production could also be reduced by Ala treatment. Ala could increase permeability of C. albicans cell membrane and ROS contribute to the antifungal activity of Ala. Overall, the present study suggests that Ala may provide a promising candidate for developing antifungal drugs against C. albicans infections.

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“…Decreased phagocytic activity might be restored by medications activating phagocytosis ( 30 – 32 ). On the other hand, overwhelming phagocytosis might be reduced by inhibiting medications ( 33 , 34 ). However, septic complications after trauma do not necessarily have to be caused by reduced or overstimulated phagocytosis itself.…”

Section: Discussionmentioning

confidence: 99%

Alterations of Phagocytic Activity and Capacity in Granulocytes and Monocytes Depend on the Pathogen Strain in Porcine Polytrauma

et al. 2021

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Background: Polytraumatized patients undergo a strong immunological stress upon insult. Phagocytes (granulocytes and monocytes) play a substantial role in immunological defense against bacteria, fungi and yeast, and in the clearance of cellular debris after tissue injury. We have reported a reduced monocytes phagocytic activity early after porcine polytrauma before. However, it is unknown if both phagocyte types undergo those functional alterations, and if there is a pathogen-specific phagocytic behavior. We characterized the phagocytic activity and capacity of granulocytes and monocytes after polytrauma.Methods: Eight pigs (Sus scrofa) underwent polytrauma consisting of lung contusion, liver laceration, tibial fracture and hemorrhagic shock with fluid resuscitation and fracture fixation with external fixator. Intensive care treatment including mechanical ventilation for 72 h followed. Phagocytic activity and capacity were investigated using an in vitro ex vivo whole blood stimulation phagocytosis assays before trauma, after surgery, 24, 48, and 72 h after trauma. Blood samples were stimulated with Phorbol-12-myristate-13-acetate and incubated with FITC-labeled E. coli, S. aureus or S. cerevisiae for phagocytosis assessment by flow cytometry.Results: Early polytrauma-induced significant increase of granulocytes and monocytes declined to baseline values within 24 h. Percentage of E. coli-phagocytizing granulocytes significantly decreased after polytrauma and during further intensive care treatment, while their capacity significantly increased. Interestingly, both granulocytic phagocytic activity and capacity of S. aureus significantly decreased after trauma, although a recovery was observed after 24 h and yet was followed by another decrease. The percentage of S. cerevisiae-phagocytizing granulocytes significantly increased after 24 h, while their impaired capacity after surgery and 72 h later was detected. Monocytic E. coli-phagocytizing percentage did not change, while their capacity increased after 24–72 h. After a significant decrease in S. aureus-phagocytizing monocytes after surgery, a significant increase after 24 and 48 h was observed without capacity alterations. No significant changes in S. cerevisiae-phagocytizing monocytes occurred, but their capacity dropped 48 and 72 h.Conclusion: Phagocytic activity and capacity of granulocytes and monocytes follow a different pattern and significantly change within 72 h after polytrauma. Both phagocytic activity and capacity show significantly different alterations depending on the pathogen strain, thus potentially indicating at certain and possibly more relevant infection causes after polytrauma.

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Antifungal Drugs Influence Neutrophil Effector Functions

Cited by 9 publications

References 72 publications

Efficacy of Voriconazole against Aspergillus fumigatus Infection Depends on Host Immune Function

Efficacy of Voriconazole against Aspergillus fumigatus Infection Depends on Host Immune Function

Antifungal effects of alantolactone onCandida albicans:anin vitrostudy

Alterations of Phagocytic Activity and Capacity in Granulocytes and Monocytes Depend on the Pathogen Strain in Porcine Polytrauma

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