Macrophages orchestrate innate immunity by phagocytosing pathogens and coordinating inflammatory responses 1 . Effective defence requires the host to discriminate between different pathogens. The specificity of innate immune recognition in Drosophila is mediated by the Toll family of receptors 2,3 ; Toll mediates anti-fungal responses, whereas 18-wheeler mediates anti-bacterial defence 4-6 . A large number of Toll homologues have been identified in mammals, and Toll-like receptor 4 is critical in responses to Gram-negative bacteria 7-11 . Here we show that Toll-like receptor 2 is recruited specifically to macrophage phagosomes containing yeast, and that a point mutation in the receptor abrogates inflammatory responses to yeast and Gram-positive bacteria, but not to Gram-negative bacteria. Thus, during the phagocytosis of pathogens, two classes of innate immune receptors cooperate to mediate host defence: phagocytic receptors, such as the mannose receptor, signal particle internalization, and the Toll-like receptors sample the contents of the vacuole and trigger an inflammatory response appropriate to defence against the specific organism.
Lipid A is the pro-inflammatory component of bacterial lipopolysaccharide, the major surface component of Gram-negative bacteria. Gram-negative bacteria alter the structure of lipid A in response to specific environmental conditions including those found upon colonization of a host. The opportunistic pathogen Pseudomonas aeruginosa synthesizes a unique hexa-acylated lipid A containing palmitate and aminoarabinose during adaptation to the cystic fibrosis airway. Different lipid A species are observed in P. aeruginosa isolated from non-cystic fibrosis associated infections. Here we report that P. aeruginosa isolates from the airway of a cystic fibrosis patient with severe pulmonary disease synthesized a novel hepta-acylated lipid A. Cystic fibrosis-specific P. aeruginosa lipid A modifications result in resistance to host antimicrobial peptides and increased recognition by human Toll-like receptor 4 (TLR4). Using P. aeruginosa lipid A with different levels of acylation, we identified a 222 amino acid region in the extracellular portion of human TLR4 that is required for the differential recognition of cystic fibrosis-specific lipid A. P. aeruginosa adaptation to the human airway may, therefore, play a fundamental role in the progressive lung damage associated with cystic fibrosis.
Patients with cystic fibrosis (CF) have altered fecal microbiomes compared to those of healthy controls. The magnitude of this dysbiosis correlates with measures of CF gastrointestinal (GI) disease, including GI inflammation and nutrient malabsorption. However, whether this dysbiosis is caused by mutations in the CFTR gene, the underlying defect in CF, or whether CF-associated dysbiosis augments GI disease was not clear. To test the relationships between CFTR dysfunction, microbes, and intestinal health, we established a germ-free (GF) CF mouse model and demonstrated that CFTR gene mutations are sufficient to alter the GI microbiome. Furthermore, flow cytometric analysis demonstrated that colonized CF mice have increased mesenteric lymph node and spleen TH17+ cells compared with non-CF mice, suggesting that CFTR defects alter adaptive immune responses. Our findings demonstrate that CFTR mutations modulate both the host adaptive immune response and the intestinal microbiome.
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