Mammalian histones facilitate antimicrobial synergy by disrupting the bacterial proton gradient and chromosome organization

Doolin, Tory; Amir, Henry M.; Duong, Leora; Rosenzweig, Rachel; Urban, Lauren A.; Bosch, Marta; Pol, Albert; Gross, Steven P.; Siryaporn, Albert

doi:10.1038/s41467-020-17699-z

Cited by 59 publications

(54 citation statements)

References 75 publications

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“…(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 ). Once inside cell, H2A reorganizes bacterial chromosomal DNA, inhibiting global transcription, acting directly on killing of bacteria ( Doolin et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…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 ). Once inside cell, H2A reorganizes bacterial chromosomal DNA, inhibiting global transcription, acting directly on killing of bacteria ( Doolin et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

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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.

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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.

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Section: Discussionmentioning

confidence: 99%

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.

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“…In this case, the two synergic partners shared a single target, but synergy may also arise from two different AMPs each one acting on their own and specific target in a concerted manner. The disruption of bacterial membranes by the human AMP LL-37 allows the histone H2A to gain access into the bacterial cytoplasm to interact with the bacterial genome, and to halt transcription [ 157 ]. Synergism is not limited to AMPs as exclusive partners; other actions or compounds may synergize with a given AMP to improve the final microbicidal aftermath.…”

Section: Synergy Of Cyanobacterial Peptidesmentioning

confidence: 99%

Cyanobacteria and Eukaryotic Microalgae as Emerging Sources of Antibacterial Peptides

et al. 2020

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Cyanobacteria and microalgae are oxygen-producing photosynthetic unicellular organisms encompassing a great diversity of species, which are able to grow under all types of extreme environments and exposed to a wide variety of predators and microbial pathogens. The antibacterial compounds described for these organisms include alkaloids, fatty acids, indoles, macrolides, peptides, phenols, pigments and terpenes, among others. This review presents an overview of antibacterial peptides isolated from cyanobacteria and microalgae, as well as their synergism and mechanisms of action described so far. Antibacterial cyanopeptides belong to different orders, but mainly from Oscillatoriales and Nostocales. Cyanopeptides have different structures but are mainly cyclic peptides. This vast peptide repertoire includes ribosomal and abundant non-ribosomal peptides, evaluated by standard conventional methodologies against pathogenic Gram-negative and Gram-positive bacteria. The antibacterial activity described for microalgal peptides is considerably scarcer, and limited to protein hydrolysates from two Chlorella species, and few peptides from Tetraselmis suecica. Despite the promising applications of antibacterial peptides and the importance of searching for new natural sources of antibiotics, limitations still persist for their pharmaceutical applications.

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“…Although the cathelicidins exhibit antimicrobial activity against bacteria, viruses, fungi, and parasites, they also modulate inflammatory responses primarily via formyl peptide receptor 2/ALX (FPR2/ALX in humans or Fpr2/3 in mice) [ 7 , 8 , 9 ]. Notably, a recent study [ 10 ] has reported that histone H2A is able exert its antimicrobial activity in bacteria in conjunction with antimicrobial peptides, LL37 and magainin-2. H2A enters into bacteria such as Escherichia coli via the pores made by LL37 and/or magainin-2, and impairs the recovery of membrane and inhibits the bacterial transcription via reorganizing the chromosome.…”

Section: Introductionmentioning

confidence: 99%

The Antimicrobial Cathelicidin CRAMP Augments Platelet Activation during Psoriasis in Mice

et al. 2020

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Platelet-associated complications including thrombosis, thrombocytopenia, and haemorrhage are commonly observed during various inflammatory diseases such as psoriasis. Although several mechanisms that may contribute to the dysfunction of platelets during inflammatory diseases have been reported, knowledge on the primary molecules/mechanisms that underpin platelet-associated complications in such conditions is not fully established. Here, we report the significance of the mouse antimicrobial cathelicidin, mouse cathelicidin-related antimicrobial peptide (mCRAMP) (an orthologue of LL37 in humans), on the modulation of platelet reactivity during psoriasis using Imiquimod-induced psoriasis in mice as an inflammatory disease model for psoriasis vulgaris in humans. The activation of platelets during psoriasis is increased as evidenced by the elevated levels of fibrinogen binding and P-selectin exposure on the surface of platelets, and the level of soluble P-selectin in the plasma of psoriatic mice. The skin and plasma of psoriatic mice displayed increased levels of mCRAMP. Moreover, the plasma of psoriatic mice augmented the activation of platelets obtained from healthy mice. The effect of mCRAMP is partially mediated through formyl peptide receptor 2/3 (Fpr2/3, the orthologue to human FPR2/ALX) in platelets as a significant reduction in their activation was observed when FPR2/ALX-selective inhibitors such as WRW4 or Fpr2/3-deficient mouse platelets were used in these assays. Since the level of antimicrobial cathelicidin is increased in numerous inflammatory diseases such as psoriasis, atherosclerosis, and inflammatory bowel disease, the results of this study point towards a critical role for antimicrobial cathelicidin and FPR2/ALX in the development of platelet-related complications in such diseases.

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Mammalian histones facilitate antimicrobial synergy by disrupting the bacterial proton gradient and chromosome organization

Cited by 59 publications

References 75 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

Cyanobacteria and Eukaryotic Microalgae as Emerging Sources of Antibacterial Peptides

The Antimicrobial Cathelicidin CRAMP Augments Platelet Activation during Psoriasis in Mice

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