The Rab32/BLOC-3–dependent pathway mediates host defense against different pathogens in human macrophages

Baldassarre, M. et al. (2021) The Rab32/BLOC-3–dependent pathway mediates host defense against different pathogens in human macrophages. Science Advances, 7(3), eabb1795. (doi: 10.1126/sciadv.abb1795) (PMID:33523895) (PMCID:PMC7810368)

Abstract

Macrophages provide a first line of defense against microorganisms, and while some mechanisms to kill pathogens such as the oxidative burst are well described, others are still undefined or unknown. Here, we report that the Rab32 guanosine triphosphatase and its guanine nucleotide exchange factor BLOC-3 (biogenesis of lysosome-related organelles complex–3) are central components of a trafficking pathway that controls both bacterial and fungal intracellular pathogens. This host-defense mechanism is active in both human and murine macrophages and is independent of well-known antimicrobial mechanisms such as the NADPH (reduced form of nicotinamide adenine dinucleotide phosphate)–dependent oxidative burst, production of nitric oxide, and antimicrobial peptides. To survive in human macrophages, Salmonella Typhi actively counteracts the Rab32/BLOC-3 pathway through its Salmonella pathogenicity island-1–encoded type III secretion system. These findings demonstrate that the Rab32/BLOC-3 pathway is a novel and universal host-defense pathway and protects mammalian species from various pathogens.

• Item Type: Articles
• Additional Information: Funding: This work was supported by the Wellcome Trust (Seed Award 109680/Z/15/Z), the European Union’s Horizon 2020 ERC consolidator award (2016-726152-TYPHI), the BBSRC (BB/N017854/1), the Royal Society (RG150386), and Tenovus Scotland (G14/19) to S.S. V.S.-C. was recipient of a European Union’s Horizon 2020 research and innovation programme Marie Skłodowska-Curie Fellowship (706040_KILLINGTYPHI). G.D.B., D.M.R., and I.M.D. were supported by the University of Aberdeen, Wellcome Trust (102705), and the MRC Centre for Medical Mycology (MR/N006364) (currently at the University of Exeter).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Balci, Dr Arda
• Authors: Baldassarre, M., Solano-Collado, V., Balci, A., Colamarino, R. A., Dambuza, I. M., Reid, D. M., Wilson, H. M., Brown, G. D., Mukhopadhyay, S., Dougan, G., and Spanò, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Science Advances
• Publisher: American Association for the Advancement of Science
• ISSN: 2375-2548
• ISSN (Online): 2375-2548
• Copyright Holders: Copyright: © 2021 The Authors
• First Published: First published in Science Advances 7(3): eabb1795
• Publisher Policy: Reproduced under a Creative Commons licence