Pseudomonas aeruginosa Lipid A Structural Variants Induce Altered Immune Responses.

Publisher: American Thoracic Society Country of Publication: United States NLM ID: 8917225 Publication Model: Print Cited Medium: Internet ISSN: 1535-4989 (Electronic) Linking ISSN: 10441549 NLM ISO Abbreviation: Am J Respir Cell Mol Biol Subsets: MEDLINE

Publication: 2000- : New York, NY : American Thoracic Society
Original Publication: [New York, NY : The Association, [c1989-

Pseudomonas aeruginosa*/immunology ; Lipid A*/metabolism ; Lipid A*/immunology ; Cystic Fibrosis*/microbiology ; Cystic Fibrosis*/immunology ; Cystic Fibrosis*/metabolism ; Pseudomonas Infections*/immunology ; Pseudomonas Infections*/microbiology ; Pseudomonas Infections*/metabolism; Humans ; Toll-Like Receptor 4/metabolism ; Toll-Like Receptor 4/immunology ; Cytokines/metabolism ; Macrophages/immunology ; Macrophages/metabolism ; Macrophages/microbiology ; Bronchoalveolar Lavage Fluid/immunology ; Lung/microbiology ; Lung/immunology ; Lung/metabolism

Pseudomonas aeruginosa causes chronic lung infection in cystic fibrosis (CF), resulting in structural lung damage and progressive pulmonary decline. P. aeruginosa in the CF lung undergoes numerous changes, adapting to host-specific airway pressures while establishing chronic infection. P. aeruginosa undergoes lipid A structural modification during CF chronic infection that is not seen in any other disease state. Lipid A, the membrane anchor of LPS (i.e., endotoxin), comprises the majority of the outer membrane of Gram-negative bacteria and is a potent Toll-like receptor 4 (TLR4) agonist. The structure of P. aeruginosa lipid A is intimately linked with its recognition by TLR4 and subsequent immune response. Prior work has identified P. aeruginosa strains with altered lipid A structures that arise during chronic CF lung infection; however, the impact of the P. aeruginosa lipid A structure on airway disease has not been investigated. Here, we show that P. aeruginosa lipid A lacks PagL-mediated deacylation during human airway infection using a direct-from-sample mass spectrometry approach on human BAL fluid. This structure triggers increased proinflammatory cytokine production by primary human macrophages. Furthermore, alterations in lipid A 2-hydroxylation impact cytokine response in a site-specific manner, independent of CF transmembrane conductance regulator function. It is interesting that there is a CF-specific reduction in IL-8 secretion within the epithelial-cell compartment that only occurs in CF bronchial epithelial cells when infected with CF-adapted P. aeruginosa that lacks PagL-mediated lipid A deacylation. Taken together, we show that P. aeruginosa alters its lipid A structure during acute lung infection and that this lipid A structure induces stronger signaling through TLR4.

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T32HL007586 United States HL NHLBI NIH HHS; T32 AI162579 United States AI NIAID NIH HHS; R01Al147314 United States National Institute of Allergy and Infectious Diseases; T32 HL007586 United States HL NHLBI NIH HHS; HOFSTA23H0 United States Cystic Fibrosis Foundation; T32AI162579 United States National Institute of Allergy and Infectious Diseases; ERNST23G0 United States Cystic Fibrosis Foundation; R01Al104895 United States National Institute of Allergy and Infectious Diseases

Keywords: LPS; Pseudomonas; TLR4; airway adaptation; cystic fibrosis

0 (Lipid A)
0 (Toll-Like Receptor 4)
0 (Cytokines)
0 (TLR4 protein, human)

Date Created: 20240424 Date Completed: 20240801 Latest Revision: 20240807

20240807

PMC11299085

10.1165/rcmb.2024-0059OC

38656811