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© Institut Pasteur et Institut Imagine
Scanning electron micrograph of segmented filamentous bacterium (SFB). Segmented filamentous bacteria (SFB) are bacteria from the Clostridiaceae family that colonize the intestines of many species, likely including humans, without causing disease; they live in symbiosis with epithelial cells and are involved in the maturation of intestinal immunity.
Publication : mBio

Targets the Host Endosome Recycling Pathway during the Biogenesis of the -Containing Vacuole To Avoid Killing by Macrophages

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in mBio - 20 Feb 2018

Connor MG, Pulsifer AR, Chung D, Rouchka EC, Ceresa BK, Lawrenz MB

Link to Pubmed [PMID] – 29463656

MBio 2018 02;9(1)

has evolved many strategies to evade the innate immune system. One of these strategies is the ability to survive within macrophages. Upon phagocytosis, prevents phagolysosome maturation and establishes a modified compartment termed the -containing vacuole (YCV). actively inhibits the acidification of this compartment, and eventually, the YCV transitions from a tight-fitting vacuole into a spacious replicative vacuole. The mechanisms to generate the YCV have not been defined. However, we hypothesized that YCV biogenesis requires interactions with specific host factors to subvert normal vesicular trafficking. In order to identify these factors, we performed a genome-wide RNA interference (RNAi) screen to identify host factors required for survival in macrophages. This screen revealed that 71 host proteins are required for intracellular survival of Of particular interest was the enrichment for genes involved in endosome recycling. Moreover, we demonstrated that actively recruits Rab4a and Rab11b to the YCV in a type three secretion system-independent manner, indicating remodeling of the YCV by to resemble a recycling endosome. While recruitment of Rab4a was necessary to inhibit YCV acidification and lysosomal fusion early during infection, Rab11b appeared to contribute to later stages of YCV biogenesis. We also discovered that disrupts global host endocytic recycling in macrophages, possibly through sequestration of Rab11b, and this process is required for bacterial replication. These data provide the first evidence that targets the host endocytic recycling pathway to avoid phagolysosomal maturation and generate the YCV. can infect and survive within macrophages. However, the mechanisms that the bacterium use to subvert killing by these phagocytes have not been defined. To provide a better understanding of these mechanisms, we used an RNAi approach to identify host factors required for intracellular survival. This approach revealed that the host endocytic recycling pathway is essential for to avoid clearance by the macrophage. We further demonstrate that remodels the phagosome to resemble a recycling endosome, allowing the bacterium to avoid the normal phagolysosomal maturation pathway. Moreover, we show that infection with disrupts normal recycling in the macrophage and that disruption is required for bacterial replication. These findings provide the first evidence that targets the host endocytic recycling pathway in order to evade killing by macrophages.

https://www.ncbi.nlm.nih.gov/pubmed/29463656