Human Antimicrobial RNases Inhibit Intracellular Bacterial Growth and Induce Autophagy in Mycobacteria-Infected Macrophages

Lu, Lu; Arranz-Trullén, Javier; Prats-Ejarque, Guillem; Pulido, David; Bhakta, Sanjib; Boix, Ester

doi:10.3389/fimmu.2019.01500

Cited by 26 publications

(59 citation statements)

References 84 publications

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“…Previously, our research group designed and explored the mechanism of action of a novel hybrid ribonuclease RNase 3/1, towards Gram-negative microorganisms [15]. Additionally, numerous studies have demonstrated the effective activity of the human RNase 3 to inhibit the intracellular growth of several microorganisms, including Mycobacterium [16] and even the proliferation of biofilm structures of P. aeruginosa [12]. In parallel, we have developed a nanoplatform based on modified magnetite nanoparticles (MNPs) for the efficient immobilization of antimicrobial and cell-penetrating molecules.…”

Section: Discussionmentioning

confidence: 99%

“…Although the catalytic activity of the protein was reduced, the antibacterial activity was maintained and increased After immobilization on MNP. Recent studies have demonstrated that indeed, the antimicrobial and catalytic activities appear unrelated [16,86]. Finally, it should be noted that the obtained nanobioconjugates were prepared at a single RNases:MNPs ratio, as detailed in the Materials and Methods section.…”

Section: Discussionmentioning

confidence: 99%

“…Besides, RNase 3 was proved effective against macrophage intracellular infection. Interestingly, we have demonstrated the high performance of RNase 3, not only in bacterial infection removal but also in internalization within macrophage cells and autophagy activation [ 16 ]. In this context, we designed an RNase 3/1 hybrid that combines the unique features of RNase 3 and the high catalytic activity and ribonuclease inhibitor affinity of RNase 1 and tested the construct in an in vitro experimental evolution test with Acinetobacter baumannii , where it demonstrated its ability to delay the acquisition of colistin resistance [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Magnetite Nanoparticles Functionalized with RNases against Intracellular Infection of Pseudomonas aeruginosa

et al. 2020

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Current treatments against bacterial infections have severe limitations, mainly due to the emergence of resistance to conventional antibiotics. In the specific case of Pseudomonas aeruginosa strains, they have shown a number of resistance mechanisms to counter most antibiotics. Human secretory RNases from the RNase A superfamily are proteins involved in a wide variety of biological functions, including antimicrobial activity. The objective of this work was to explore the intracellular antimicrobial action of an RNase 3/1 hybrid protein that combines RNase 1 high catalytic and RNase 3 bactericidal activities. To achieve this, we immobilized the RNase 3/1 hybrid on Polyetheramine (PEA)-modified magnetite nanoparticles (MNPs). The obtained nanobioconjugates were tested in macrophage-derived THP-1 cells infected with Pseudomonas aeruginosa PAO1. The obtained results show high antimicrobial activity of the functionalized hybrid protein (MNP-RNase 3/1) against the intracellular growth of P. aeruginosa of the functionalized hybrid protein. Moreover, the immobilization of RNase 3/1 enhances its antimicrobial and cell-penetrating activities without generating any significant cell damage. Considering the observed antibacterial activity, the immobilization of the RNase A superfamily and derived proteins represents an innovative approach for the development of new strategies using nanoparticles to deliver antimicrobials that counteract P. aeruginosa intracellular infection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Magnetite Nanoparticles Functionalized with RNases against Intracellular Infection of Pseudomonas aeruginosa

et al. 2020

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“…Indeed, RNase3 internalization is observed in treated yeast cells and protozoa [8,13]. Besides, RNase3 can enter the macrophage and eradicate the intracellular dwelling bacteria [14]. On the other hand, the protein antiviral activity on single stranded RNA viruses has been directly correlated to its ribonucleolytic action [9].…”

Section: Introductionmentioning

confidence: 99%

Human RNase3 immune modulation by catalytic-dependent and independent modes in a macrophage-cell line infection model

Wei

Prats-Ejarque

et al. 2020

Cell. Mol. Life Sci.

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The human RNase3 is a member of the RNaseA superfamily involved in host immunity. RNase3 is expressed by leukocytes and shows broad-spectrum antimicrobial activity. Together with a direct antimicrobial action, RNase3 exhibits immunomodulatory properties. Here, we have analysed the transcriptome of macrophages exposed to the wild-type protein and a catalytic-defective mutant (RNase3-H15A). The analysis of differently expressed genes (DEGs) in treated THP1-derived macrophages highlighted a common pro-inflammatory “core-response” independent of the protein ribonucleolytic activity. Network analysis identified the epidermal growth factor receptor (EGFR) as the main central regulatory protein. Expression of selected DEGs and MAPK phosphorylation were inhibited by an anti-EGFR antibody. Structural analysis suggested that RNase3 activates the EGFR pathway by direct interaction with the receptor. Besides, we identified a subset of DEGs related to the protein ribonucleolytic activity, characteristic of virus infection response. Transcriptome analysis revealed an early pro-inflammatory response, not associated to the protein catalytic activity, followed by a late activation in a ribonucleolytic-dependent manner. Next, we demonstrated that overexpression of macrophage endogenous RNase3 protects the cells against infection by Mycobacterium aurum and the human respiratory syncytial virus. Comparison of cell infection profiles in the presence of Erlotinib, an EGFR inhibitor, revealed that the receptor activation is required for the antibacterial but not for the antiviral protein action. Moreover, the DEGs related and unrelated to the protein catalytic activity are associated to the immune response to bacterial and viral infection, respectively. We conclude that RNase3 modulates the macrophage defence against infection in both catalytic-dependent and independent manners.

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“…The antimicrobial properties of this variant are carried out by inducing bacteria agglutination (66). Furthermore, RNase 6, as well as RNase 3, is highly effective against Mycobacterium aurum by inducing an autophagy process in the infected macrophages (67).…”

Section: Introductionmentioning

confidence: 99%

Biological Activities of Secretory RNases: Focus on Their Oligomerization to Design Antitumor Drugs

Gotte

Menegazzi

2019

Front. Immunol.

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Ribonucleases (RNases) are a large number of enzymes gathered into different bacterial or eukaryotic superfamilies. Bovine pancreatic RNase A, bovine seminal BS-RNase, human pancreatic RNase 1, angiogenin (RNase 5), and amphibian onconase belong to the pancreatic type superfamily, while binase and barnase are in the bacterial RNase N1/T1 family. In physiological conditions, most RNases secreted in the extracellular space counteract the undesired effects of extracellular RNAs and become protective against infections. Instead, if they enter the cell, RNases can digest intracellular RNAs, becoming cytotoxic and having advantageous effects against malignant cells. Their biological activities have been investigated either in vitro, toward a number of different cancer cell lines, or in some cases in vivo to test their potential therapeutic use. However, immunogenicity or other undesired effects have sometimes been associated with their action. Nevertheless, the use of RNases in therapy remains an appealing strategy against some still incurable tumors, such as mesothelioma, melanoma, or pancreatic cancer. The RNase inhibitor (RI) present inside almost all cells is the most efficacious sentry to counteract the ribonucleolytic action against intracellular RNAs because it forms a tight, irreversible and enzymatically inactive complex with many monomeric RNases. Therefore, dimerization or multimerization could represent a useful strategy for RNases to exert a remarkable cytotoxic activity by evading the interaction with RI by steric hindrance. Indeed, the majority of the mentioned RNases can hetero-dimerize with antibody derivatives, or even homo-dimerize or multimerize, spontaneously or artificially. This can occur through weak interactions or upon introducing covalent bonds. Immuno-RNases, in particular, are fusion proteins representing promising drugs by combining high target specificity with easy delivery in tumors. The results concerning the biological features of many RNases reported in the literature are described and discussed in this review. Furthermore, the activities displayed by some RNases forming oligomeric complexes, the mechanisms driving toward these supramolecular structures, and the biological rebounds connected are analyzed. These aspects are offered with the perspective to suggest possible efficacious therapeutic applications for RNases oligomeric derivatives that could contemporarily lack, or strongly reduce, immunogenicity and other undesired side-effects.

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Human Antimicrobial RNases Inhibit Intracellular Bacterial Growth and Induce Autophagy in Mycobacteria-Infected Macrophages

Cited by 26 publications

References 84 publications

Magnetite Nanoparticles Functionalized with RNases against Intracellular Infection of Pseudomonas aeruginosa

Magnetite Nanoparticles Functionalized with RNases against Intracellular Infection of Pseudomonas aeruginosa

Human RNase3 immune modulation by catalytic-dependent and independent modes in a macrophage-cell line infection model

Biological Activities of Secretory RNases: Focus on Their Oligomerization to Design Antitumor Drugs

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