Antifungal Activity of Antimicrobial Peptides and Proteins against Aspergillus fumigatus

Ballard, Eloise; Yucel, Raif; Melchers, Willem J. G.; Brown, Alistair J. P.; Verweij, Paul E.; Warris, Adilia

doi:10.3390/jof6020065

Cited by 21 publications

(36 citation statements)

References 59 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ballard et al. (2020) ( Ballard et al., 2020 ) demonstrated that lysozyme and histones inhibited hyphal metabolic activity in A. fumigatus isolates in a dose-dependent manner, and imaging flow cytometry revealed that histones inhibited the germination of A. fumigatus conidia. Recently, it was demonstrated that histone H2A enters Escherichia coli and S. aureus through membrane pores formed by the AMPs LL-37 and magainin-2, depolarizing the bacterial membrane potential, and impairing membrane recovery ( Doolin et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Paracoccidioides brasiliensis Releases a DNase-Like Protein That Degrades NETs and Allows for Fungal Escape

Zonta

Dezen

Coletta

et al. 2021

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Paracoccidioidomycosis is a systemic fungal disease, considered endemic in Latin America. Its etiological agents, fungi of the Paracoccidioides complex, have restricted geographic habitat, conidia as infecting form, and thermo-dimorphic characteristics. Polymorphonuclear neutrophils (PMNs) are responsible for an important defense response against fungus, releasing Neutrophil Extracellular Traps (NETs), which can wrap and destroy the yeasts. However, it has been described that some pathogens are able to evade from these DNA structures by releasing DNase as an escape mechanism. As different NETs patterns have been identified in PMNs cultures challenged with different isolates of Paracoccidioides brasiliensis, the general objective of this study was to identify if different patterns of NETs released by human PMNs challenged with Pb18 (virulent) and Pb265 (avirulent) isolates would be correlated with fungal ability to produce a DNase-like protein. To this end, PMNs from healthy subjects were isolated and challenged in vitro with both fungal isolates. The production, release, and conformation of NETs in response to the fungi were evaluated by Confocal Microscopy, Scanning Microscopy, and NETs Quantification. The identification of fungal DNase production was assessed by DNase TEST Agar, and the relative gene expression for hypothetical proteins was investigated by RT-qPCR, whose genes had been identified in the fungal genome in the GenBank (PADG_11161 and PADG_08285). It was possible to verify the NETs release by PMNs, showing different NETs formation when in contact with different isolates of the fungus. The Pb18 isolate induced the release of looser, larger, and more looking like degraded NETs compared to the Pb265 isolate, which induced the release of denser and more compact NETs. DNase TEST Agar identified the production of a DNase-like protein, showing that only Pb18 showed the capacity to degrade DNA in these plates. Besides that, we were able to identify that both PADG_08528 and PADG_11161 genes were more expressed during interaction with neutrophil by the virulent isolate, being PADG_08528 highly expressed in these cultures, demonstrating that this gene could have a greater contribution to the production of the protein. Thus, we identified that the virulent isolate is inducing more scattered and loose NETs, probably by releasing a DNase-like protein. This factor could be an important escape mechanism used by the fungus to escape the NETs action.

show abstract

Section: Discussionmentioning

confidence: 99%

Paracoccidioides brasiliensis Releases a DNase-Like Protein That Degrades NETs and Allows for Fungal Escape

Zonta

Dezen

Coletta

et al. 2021

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…Much of our current study has centered around the role of an early ROS burst in response to A. fumigatus that is dependent on Nlrx1. However, it is critical to acknowledge a number of additional non-oxidative defense strategies such as secreted peptides and proteins (47)(48)(49) may also be differentially expressed in a decreasing manner in the Nlrx1-deficient background. One broad conclusion of our study is that the functions and roles of Nlrx1 continue to extend, and these processes, such as an absence of negative regulation of glycolysis may also impact additional processes within the cell such as gene expression of defense proteins.…”

Section: Discussionmentioning

confidence: 99%

Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific

Kastelberg¹,

Ayubi²,

Tubau-Juni³

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

The Nlr family member X1 (Nlrx1) is an immuno-metabolic hub involved in mediating effective responses to virus, bacteria, fungi, cancer, and auto-immune diseases. We have previously shown that Nlrx1 is a critical regulator of immune signaling and mortality in several models of pulmonary fungal infection using the clinically relevant fungus Aspergillus fumigatus. In the absence of Nlrx1, hosts produce an enhanced Th2 response primarily by CD103+ dendritic cell populations resulting in enhanced mortality via immunopathogenesis as well as enhanced fungal burden. Here, we present our subsequent efforts showcasing loss of Nlrx1 resulting in a decreased ability of host cells to process A. fumigatus conidia in a cell-type-specific manner by BEAS-2B airway epithelial cells, alveolar macrophages, bone marrow-derived macrophages, but not bone marrow-derived neutrophils. Furthermore, loss of Nlrx1 results in a diminished ability to generate superoxide and/or generic reactive oxygen species during specific responses to fungal PAMPs, conidia, and hyphae. Analysis of glycolysis and mitochondrial function suggests that Nlrx1 is needed to appropriately shut down glycolysis in response to A. fumigatus conidia and increase glycolysis in response to hyphae in BEAS-2B cells. Blocking glycolysis and pentose phosphate pathway (PPP) via 2-DG and NADPH production through glucose-6-phosphate dehydrogenase inhibitor resulted in significantly diminished conidial processing in wild-type BEAS-2B cells to the levels of Nlrx1-deficient BEAS-2B cells. Our findings suggest a need for airway epithelial cells to generate NADPH for reactive oxygen species production in response to conidia via PPP. In context to fungal pulmonary infections, our results show that Nlrx1 plays significant roles in host defense via PPP modulation of several aspects of metabolism, particularly glycolysis, to facilitate conidia processing in addition to its critical role in regulating immune signaling.

show abstract

“…Nevertheless, further in vivo investigations are needed regarding LL-37 cytotoxicity on mammalian cells to be a potential drug candidate for combating C. auris infections ( Rather et al, 2022 ). Unfortunately, controversial results have been reported for LL-37 activity in case of Aspergillus species ( Luo et al, 2019 ; Ballard et al, 2020 ), however, cathelicin-based synthesized peptides seem to be promising antifungals against A. fumigatus ( van Eijk et al, 2020 ).…”

Section: Peptides With Antifungal Activity As Potential Therapeutic A...mentioning

confidence: 99%

COVID-19-Associated Fungal Infections: An Urgent Need for Alternative Therapeutic Approach?

Domán

Bányai

2022

Front. Microbiol.

View full text Add to dashboard Cite

Secondary fungal infections may complicate the clinical course of patients affected by viral respiratory diseases, especially those admitted to intensive care unit. Hospitalized COVID-19 patients are at increased risk of fungal co-infections exacerbating the prognosis of disease due to misdiagnosis that often result in treatment failure and high mortality rate. COVID-19-associated fungal infections caused by predominantly Aspergillus and Candida species, and fungi of the order Mucorales have been reported from several countries to become significant challenge for healthcare system. Early diagnosis and adequate antifungal therapy is essential to improve clinical outcomes, however, drug resistance shows a rising trend highlighting the need for alternative therapeutic agents. The purpose of this review is to summarize the current knowledge on COVID-19-associated mycoses, treatment strategies and the most recent advancements in antifungal drug development focusing on peptides with antifungal activity.

show abstract

Antifungal Activity of Antimicrobial Peptides and Proteins against Aspergillus fumigatus

Cited by 21 publications

References 59 publications

Paracoccidioides brasiliensis Releases a DNase-Like Protein That Degrades NETs and Allows for Fungal Escape

Paracoccidioides brasiliensis Releases a DNase-Like Protein That Degrades NETs and Allows for Fungal Escape

Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific

COVID-19-Associated Fungal Infections: An Urgent Need for Alternative Therapeutic Approach?

Contact Info

Product

Resources

About