Baldassarre Massimiliano, Solano-Collado Virtu, Balci Arda, Colamarino Rosa A, Dambuza Ivy M, Reid Delyth M, Wilson Heather M, Brown Gordon D, Mukhopadhyay Subhankar, Dougan Gordon, Spanò Stefania
Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, UK.
MRC Centre for Medical Mycology, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK.
Sci Adv. 2021 Jan 15;7(3). doi: 10.1126/sciadv.abb1795. Print 2021 Jan.
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, Typhi actively counteracts the Rab32/BLOC-3 pathway through its 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.
巨噬细胞提供了抵御微生物的第一道防线，虽然一些杀死病原体的机制，如氧化爆发，已得到充分描述，但其他机制仍未明确或未知。在此，我们报告Rab32鸟苷三磷酸酶及其鸟嘌呤核苷酸交换因子BLOC-3（溶酶体相关细胞器复合体-3的生物发生）是控制细菌和真菌细胞内病原体的运输途径的核心组成部分。这种宿主防御机制在人类和小鼠巨噬细胞中均有活性，且独立于诸如依赖烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的氧化爆发、一氧化氮的产生以及抗菌肽等知名抗菌机制。为了在人类巨噬细胞中存活，伤寒杆菌通过其1号致病岛编码的III型分泌系统积极对抗Rab32/BLOC-3途径。这些发现表明，Rab32/BLOC-3途径是一种新型的通用宿主防御途径，可保护哺乳动物免受各种病原体的侵害。
