The microbiota protects against respiratory infection via GM-CSF signaling

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 signal-regulated 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.

The role of the lung microbiota and the gut-lung axis in respiratory infectious diseases

“…Faecal transplantation by oral gavage with a normal gut microbiota restored both control of the infection in the mice and cytokines' levels in the lungs, illustrating the contribution the gut microbiota makes to lung immunity (Schuijt et al, 2016). GM-CSF levels were restored following intranasal administration of IL-17A in antibiotic-treated mice, indicating that the microbiota protects the host from respiratory pathogens via IL-17A, which in turn regulates local GM-CSF production (Brown et al, 2017). In another study, susceptibility to S. pneumoniae and K. pneumoniae infection in antibiotictreated mice correlated with reduced production of granulocytemacrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-17A in the lungs (Brown et al, 2017).…”

“…For example, GF mice are more sensitive to lung infection by Pseudomonas aeruginosa, Streptococcus pneumoniae, and Klebsiella pneumoniae (Brown et al, 2017;Fagundes et al, 2012;Fox et al, 2012). By contrast, analysis of the composition of this microbial community has been poorly explored in patients suffering from acute lung infections, such as pneumonia, probably due to the short duration of such diseases.…”

“…In particular, antibiotic-treated mice infected with S. pneumoniae suffered a defect in lung cytokine production. In another study, susceptibility to S. pneumoniae and K. pneumoniae infection in antibiotictreated mice correlated with reduced production of granulocytemacrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-17A in the lungs (Brown et al, 2017). Nevertheless, the potential role of the local, pulmonary microbiota in host defence against S. pneumoniae remains to be evaluated (Lankelma et al, 2017).…”

“…However, the beneficial role of the host microbiota during acute bacterial infections of the lungs has been demonstrated in numerous settings using GF mice. For example, GF mice are more sensitive to lung infection by Pseudomonas aeruginosa, Streptococcus pneumoniae, and Klebsiella pneumoniae (Brown et al, 2017;Fagundes et al, 2012;Fox et al, 2012). Dissection of the molecular mechanisms involved in host protection against lung infections by the microbiota has been limited because of the complication that, in addition to profound anatomical and developmental differences compared with specific pathogen-free mice, GF mice display an altered immune system (Al-Asmakh et al, 2015).…”

Housing Gnotobiotic Mice in Conventional Animal Facilities

“…GB mice have emerged as an invaluable model to elucidate key aspects of the host‐microbiota interaction in mammals (Diaz Heijtz et al., ; McVey Neufeld, Perez‐Burgos, Mao, Bienenstock, & Kunze, ; Quach, Collins, Parameswaran, McCabe, & Britton, ; Sjogren et al., ). This model has also proven itself to be of considerable value for studying pathogen‐host interactions (Brown, Sequeira, & Clarke, ; Fei & Zhao, ; Goswami, Chen, Xiaoli, Eaton, & Dudley, ; Nascimento et al., ; Soavelomandroso et al., ). All scientific activities conducted within signatory countries that involve pathogens must adhere to United Nations conventions on biosafety and biosecurity.…”