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    Human Antimicrobial RNases inhibit intracellular bacterial growth and induce Autophagy in Mycobacteria-Infected Macrophages

    Lu, L. and Arranz-Trullén, J. and Prats-Ejarque, G. and Pulido, D. and Bhakta, Sanjib and Boix, E. (2019) Human Antimicrobial RNases inhibit intracellular bacterial growth and induce Autophagy in Mycobacteria-Infected Macrophages. Frontiers In Immunology 10 , ISSN 1664-3224.

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    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.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Depositing User: Administrator
    Date Deposited: 03 Jul 2019 11:50
    Last Modified: 01 Aug 2019 18:01
    URI: http://eprints.bbk.ac.uk/id/eprint/28004

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