Neuraminidase 1-mediated desialylation of the mucin 1 ectodomain releases a decoy receptor that protects against Pseudomonas aeruginosa lung infection.

Abstract

Pseudomonas aeruginosa (Pa) expresses an adhesin, flagellin, that engages the mucin 1 (MUC1) ectodomain (ED) expressed on airway epithelia, increasing association of MUC1-ED with neuraminidase 1 (NEU1) and MUC1-ED desialylation. The MUC1-ED desialylation unmasks both cryptic binding sites for Pa and a protease recognition site, permitting its proteolytic release as a hyperadhesive decoy receptor for Pa. We found here that intranasal administration of Pa strain K (PAK) to BALB/c mice increases MUC1-ED shedding into the bronchoalveolar compartment. MUC1-ED levels increased as early as 12 h, peaked at 24-48 h with a 7.8-fold increase, and decreased by 72 h. The a-type flagellin-expressing PAK strain and the b-type flagellin-expressing PAO1 strain stimulated comparable levels of MUC1-ED shedding. A flagellin-deficient PAK mutant provoked dramatically reduced MUC1-ED shedding compared with the WT strain, and purified flagellin recapitulated the WT effect. In lung tissues, Pa increased association of NEU1 and protective protein/cathepsin A with MUC1-ED in reciprocal co-immunoprecipitation assays and stimulated MUC1-ED desialylation. NEU1-selective sialidase inhibition protected against Pa-induced MUC1-ED desialylation and shedding. In Pa-challenged mice, MUC1-ED-enriched bronchoalveolar lavage fluid (BALF) inhibited flagellin binding and Pa adhesion to human airway epithelia by up to 44% and flagellin-driven motility by >30%. Finally, Pa co-administration with recombinant human MUC1-ED dramatically diminished lung and BALF bacterial burden, proinflammatory cytokine levels, and pulmonary leukostasis and increased 5-day survival from 0% to 75%. We conclude that Pa flagellin provokes NEU1-mediated airway shedding of MUC1-ED, which functions as a decoy receptor protecting against lethal Pa lung infection.

• Authors: Erik P Lillehoj, Wei Guang, Sang W Hyun, Anguo Liu, Nicolas Hegerle, Raphael Simon, Alan S Cross, Hideharu Ishida, Irina G Luzina, Sergei P Atamas, Simeon E Goldblum
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 294 Issue 2 Pg. 662-678 (01 11 2019) ISSN: 1083-351X [Electronic] United States
• PMID: 30429216 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Mucin-1
• Flagellin
• Neu1 protein, mouse
• Neuraminidase

Topics

• Animals
• Female
• Flagellin (metabolism)
• Host-Pathogen Interactions
• Humans
• Lung (metabolism, microbiology, pathology)
• Male
• Mice, Inbred BALB C
• Mucin-1 (metabolism)
• Neuraminidase (metabolism)
• Pneumonia, Bacterial (metabolism, microbiology, pathology)
• Protective Factors
• Pseudomonas Infections (metabolism, microbiology, pathology)
• Pseudomonas aeruginosa (physiology)