Decoy exosomes provide protection against bacterial toxins

The production of pore-forming toxins that disrupt the plasma membrane of host cells is a common virulence strategy for bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) . It is unclear, however, whether host species possess innate immune mechanisms that can neutralize p...

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Bibliographic Details
Published in:Nature (London) 2020-03, Vol.579 (7798), p.260-264
Main Authors: Keller, Matthew D, Ching, Krystal L, Liang, Feng-Xia, Dhabaria, Avantika, Tam, Kayan, Ueberheide, Beatrix M, Unutmaz, Derya, Torres, Victor J, Cadwell, Ken
Format: Article
Language:English
Subjects:
A549 Cells
Acidification
ADAM10 Protein - metabolism
Analysis
Animals
Autophagy
Autophagy-Related Proteins - metabolism
Bacteria
Bacterial toxins
Bacterial Toxins - metabolism
Bacterial Toxins - pharmacology
Bacterial vesicles
Biodegradation
Biosynthesis
Cell adhesion & migration
Cell Survival - drug effects
Control
CpG islands
Decoys
Deoxyribonucleic acid
DNA
DNA, Bacterial - pharmacology
Drug resistance
Exosomes
Exosomes - drug effects
Exosomes - metabolism
Exosomes - ultrastructure
Extracellular vesicles
Female
HEK293 Cells
Host-bacteria relationships
Humans
Infections
Male
Metalloproteinase
Methicillin-Resistant Staphylococcus aureus - pathogenicity
Methicillin-Resistant Staphylococcus aureus - physiology
Mice
Mice, Inbred C57BL
Phagocytosis
Pore formation
Proteins
Staphylococcal Infections - mortality
Staphylococcus aureus
Staphylococcus infections
Streptococcus infections
Toxins
Virulence
α-Toxin
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Summary:The production of pore-forming toxins that disrupt the plasma membrane of host cells is a common virulence strategy for bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) . It is unclear, however, whether host species possess innate immune mechanisms that can neutralize pore-forming toxins during infection. We previously showed that the autophagy protein ATG16L1 is necessary for protection against MRSA strains encoding α-toxin -a pore-forming toxin that binds the metalloprotease ADAM10 on the surface of a broad range of target cells and tissues . Autophagy typically involves the targeting of cytosolic material to the lysosome for degradation. Here we demonstrate that ATG16L1 and other ATG proteins mediate protection against α-toxin through the release of ADAM10 on exosomes-extracellular vesicles of endosomal origin. Bacterial DNA and CpG DNA induce the secretion of ADAM10-bearing exosomes from human cells as well as in mice. Transferred exosomes protect host cells in vitro by serving as scavengers that can bind multiple toxins, and improve the survival of mice infected with MRSA in vivo. These findings indicate that ATG proteins mediate a previously unknown form of defence in response to infection, facilitating the release of exosomes that serve as decoys for bacterially produced toxins.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-020-2066-6