Biochemistry and Pharmacology - Research Publications

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Author: Edgington-Mitchell, Laura × Author: Newton, Hayley × Start date: 2020 × End date: 2024 ×

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    Eat, prey, love: Pathogen-mediated subversion of lysosomal biology.
    Bird, LE ; Edgington-Mitchell, LE ; Newton, HJ (Elsevier BV, 2023-08)
    The mammalian lysosome is classically considered the 'garbage can' of the cell, contributing to clearance of infection through its primary function as a degradative organelle. Intracellular pathogens have evolved several strategies to evade contact with this harsh environment through subversion of endolysosomal trafficking or escape into the cytosol. Pathogens can also manipulate pathways that lead to lysosomal biogenesis or alter the abundance or activity of lysosomal content. This pathogen-driven subversion of lysosomal biology is highly dynamic and depends on a range of factors, including cell type, stage of infection, intracellular niche and pathogen load. The growing body of literature in this field highlights the nuanced and complex relationship between intracellular pathogens and the host lysosome, which is critical for our understanding of infection biology.
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    Lysosomal degradation products induce Coxiella burnetii virulence
    Newton, P ; Thomas, DR ; Reed, SCO ; Lau, N ; Xu, B ; Ong, SY ; Pasricha, S ; Madhamshettiwar, PB ; Edgington-Mitchell, LE ; Simpson, KJ ; Roy, CR ; Newton, HJ (NATL ACAD SCIENCES, 2020-03-24)
    Coxiella burnetii is an intracellular pathogen that replicates in a lysosome-like vacuole through activation of a Dot/Icm-type IVB secretion system and subsequent translocation of effectors that remodel the host cell. Here a genome-wide small interfering RNA screen and reporter assay were used to identify host proteins required for Dot/Icm effector translocation. Significant, and independently validated, hits demonstrated the importance of multiple protein families required for endocytic trafficking of the C. burnetii-containing vacuole to the lysosome. Further analysis demonstrated that the degradative activity of the lysosome created by proteases, such as TPP1, which are transported to the lysosome by receptors, such as M6PR and LRP1, are critical for C. burnetii virulence. Indeed, the C. burnetii PmrA/B regulon, responsible for transcriptional up-regulation of genes encoding the Dot/Icm apparatus and a subset of effectors, induced expression of a virulence-associated transcriptome in response to degradative products of the lysosome. Luciferase reporter strains, and subsequent RNA-sequencing analysis, demonstrated that particular amino acids activate the C. burnetii PmrA/B two-component system. This study has further enhanced our understanding of C. burnetii pathogenesis, the host-pathogen interactions that contribute to bacterial virulence, and the different environmental triggers pathogens can sense to facilitate virulence.