Lysosomal degradation products induce Coxiella burnetii virulence.

Proceedings of the National Academy of Sciences of the United States of America
Patrice NewtonHayley J Newton

Abstract

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...Continue Reading

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Citations

Dec 8, 2020·Frontiers in Cellular and Infection Microbiology·Julian PechsteinAnja Lührmann
Dec 22, 2020·Frontiers in Cellular and Infection Microbiology·Lidia Szulc-DąbrowskaFelix N Toka
Dec 1, 2020·Frontiers in Cellular and Infection Microbiology·David R ThomasHayley J Newton
Mar 29, 2021·Cellular Microbiology·Samuel SteinerCraig R Roy

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Methods Mentioned

BETA
GTPases
transfection
fluorescence microscopy
RNA-seq
FRET
Assay

Software Mentioned

NT
siOTP
PANTHER
HCS Studio

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