The microbiota protects against respiratory infection via GM-CSF signaling
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Supporting information
Author(s)
Clarke, TB
Brown, RL
Sequeira, RL
Type
Journal Article
Abstract
The microbiota promotes resistance to respiratory infection, but the mechanistic basis for
this is poorly defined. Here, we identify members of the microbiota that protect against
respiratory infection by the major human pathogens Streptococcus pneumoniae and Klebsiella
pneumoniae. We show that the microbiota enhances respiratory defenses via
granulocyte–macrophage colony-stimulating factor (GM-CSF) signaling, which stimulates
pathogen killing and clearance by alveolar macrophages through extracellular signalregulated
kinase signaling. Increased pulmonary GM-CSF production in response to infection
is primed by the microbiota through interleukin-17A. By combining models of commensal
colonization in antibiotic-treated and germ-free mice, using cultured commensals from the
Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria phyla, we found that potent
Nod-like receptor-stimulating bacteria in the upper airway (Staphylococcus aureus and Staphylococcus
epidermidis) and intestinal microbiota (Lactobacillus reuteri, Enterococcus faecalis,
Lactobacillus crispatus and Clostridium orbiscindens) promote resistance to lung infection
through Nod2 and GM-CSF. Our data reveal the identity, location, and properties of bacteria
within the microbiota that regulate lung immunity, and delineate the host signaling axis they
activate to protect against respiratory infection.
this is poorly defined. Here, we identify members of the microbiota that protect against
respiratory infection by the major human pathogens Streptococcus pneumoniae and Klebsiella
pneumoniae. We show that the microbiota enhances respiratory defenses via
granulocyte–macrophage colony-stimulating factor (GM-CSF) signaling, which stimulates
pathogen killing and clearance by alveolar macrophages through extracellular signalregulated
kinase signaling. Increased pulmonary GM-CSF production in response to infection
is primed by the microbiota through interleukin-17A. By combining models of commensal
colonization in antibiotic-treated and germ-free mice, using cultured commensals from the
Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria phyla, we found that potent
Nod-like receptor-stimulating bacteria in the upper airway (Staphylococcus aureus and Staphylococcus
epidermidis) and intestinal microbiota (Lactobacillus reuteri, Enterococcus faecalis,
Lactobacillus crispatus and Clostridium orbiscindens) promote resistance to lung infection
through Nod2 and GM-CSF. Our data reveal the identity, location, and properties of bacteria
within the microbiota that regulate lung immunity, and delineate the host signaling axis they
activate to protect against respiratory infection.
Date Issued
2017-11-15
Date Acceptance
2017-10-17
Citation
Nature Communications, 2017, 8, pp.1-11
ISSN
2041-1723
Publisher
Nature Publishing Group
Start Page
1
End Page
11
Journal / Book Title
Nature Communications
Volume
8
Copyright Statement
This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit http://creativecommons.org/
licenses/by/4.0/.
© The Author(s) 2017
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit http://creativecommons.org/
licenses/by/4.0/.
© The Author(s) 2017
License URL
Sponsor
Wellcome Trust
Identifier
https://www.nature.com/articles/s41467-017-01803-x
Grant Number
107660/Z/15/Z
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
GUT MICROBIOTA
BACTERIAL-INFECTION
STREPTOCOCCUS-PNEUMONIAE
COMMENSAL MICROBIOTA
IMMUNE-RESPONSES
INNATE IMMUNITY
HOST-DEFENSE
DISEASE
NOD1
COLONIZATION
Animals
Granulocyte-Macrophage Colony-Stimulating Factor
HEK293 Cells
Humans
Interleukin-17
Klebsiella pneumoniae
Lung
Macrophages, Alveolar
Mice, Inbred C57BL
Mice, Knockout
Microbial Interactions
Microbiota
Respiratory Tract Infections
Signal Transduction
Streptococcus pneumoniae
Lung
Macrophages, Alveolar
Animals
Mice, Inbred C57BL
Mice, Knockout
Humans
Klebsiella pneumoniae
Streptococcus pneumoniae
Respiratory Tract Infections
Granulocyte-Macrophage Colony-Stimulating Factor
Interleukin-17
Signal Transduction
Microbial Interactions
HEK293 Cells
Microbiota
Publication Status
Published
Article Number
1512
Date Publish Online
2017-11-15