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 flagellindeficient 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.

Defensive Properties of Mucin Glycoproteins during Respiratory Infections—Relevance for SARS-CoV-2

“…In another study, it was shown that the immunosuppressive effect of MUC1 on TLR5 in bronchial epithelial cells is mediated by prevention of recruitment of MyD88 to TLR5 and inhibition of downstream signaling ( 34 ). A recent study reported that the extracellular domain of MUC1 can act as a releasable decoy molecule during P. aeruginosa infection, thereby restricting pathogen adherence to the epithelial surface ( 35 ).…”

Role of the mucins in pathogenesis of COPD: implications for therapy

“…Infection with P. aeruginosa strain K in mice increased Muc1 expression in BAL compared to sham infection [55]. Muc1 −/− mice had reduced colonization of P. aeruginosa (p<0.05) due to increased clearance by heightened early inflammatory responses to the infection, compared to wild-type mice [60].…”

“…P. aeruginosa engages the MUC1 ectodomain through its adhesin, flagellin [55,56]. In primary human alveolar macrophages isolated from the BAL of healthy subjects and human monocytic cell line (THP-1 cells), P. aeruginosa infection significantly increased MUC1 expression compared to uninfected cells [57].…”

Decoy Technology as a Promising Therapeutic Tool for Atherosclerosis

“…Decoy peptides are applied throughout various fields of research and have been demonstrated as an anticancer agent via a decoy receptor for Wnt ligands [ 34 , 36 ]. Importantly, decoy receptors constitute a novel and relatively unknown target for development of antiviral drugs [ 37 ] or as a therapeutic tool for inhibition of bacterial infections [ 38 ]. Moreover, decoy peptides are employed as a novel class of therapeutics for combatting neurotoxic envenoming [ 39 ].…”