Human antimicrobial RNases inhibit intracellular bacterial growth and induce autophagy in mycobacteria-infected macrophages
Lu, Lu (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Arranz Trullén, Javier (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Prats-Ejarque, Guillem (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pulido-Gomez, David (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Bhakta, Sanjib (University of London. Department of Biological Sciences)
Boix i Borràs, Esther (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2019
Abstract:	The development of novel treatment against tuberculosis is a priority global health challenge. Antimicrobial proteins and peptides offer a multifaceted mechanism suitable to fight bacterial resistance. Within the RNaseA superfamily there is a group of highly cationic proteins secreted by innate immune cells with anti-infective and immune-regulatory properties. In this work, we have tested the human canonical members of the RNase family using a spot-culture growth inhibition assay based mycobacteria-infected macrophage model for evaluating their anti-tubercular properties. Out of the seven tested recombinant human RNases, we have identified two members, RNase3 and RNase6, which were highly effective against Mycobacterium aurum extra- and intracellularly and induced an autophagy process. We observed the proteins internalization within macrophages and their capacity to eradicate the intracellular mycobacterial infection at a low micro-molar range. Contribution of the enzymatic activity was discarded by site-directed mutagenesis at the RNase catalytic site. The protein induction of autophagy was analyzed by RT-qPCR, western blot, immunofluorescence, and electron microscopy. Specific blockage of auto-phagosome formation and maturation reduced the protein's ability to eradicate the infection. In addition, we found that the M. aurum infection of human THP1 macrophages modulates the expression of endogenous RNase3 and RNase6, suggesting a function in vivo. Overall, our data anticipate a biological role for human antimicrobial RNases in host response to mycobacterial infections and set the basis for the design of novel anti-tubercular drugs.
Grants:	Ministerio de Economía y Competitividad SAF2015-66007P Agència de Gestió d'Ajuts Universitaris i de Recerca 2016/PROD-00060
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Antimicrobial peptides ; Ribonucleases ; Tuberculosis ; Macrophage ; Autophagy
Published in:	Frontiers in immunology, Vol. 10 (July 2019) , art. 1500, ISSN 1664-3224

DOI: 10.3389/fimmu.2019.01500
PMID: 31312205

17 p, 3.1 MB

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