MUC1 ectodomain is a flagellin-targeting decoy receptor and biomarker operative during Pseudomonas aeruginosa lung infection

Abstract

We previously reported that flagellin-expressing Pseudomonas aeruginosa (Pa) provokes NEU1 sialidase-mediated MUC1 ectodomain (MUC1-ED) desialylation and MUC1-ED shedding from murine lungs in vivo. Here, we asked whether Pa in the lungs of patients with ventilator-associated pneumonia might also increase MUC1-ED shedding. The levels of MUC1-ED and Pa-expressed flagellin were dramatically elevated in bronchoalveolar lavage fluid (BALF) harvested from Pa-infected patients, and each flagellin level, in turn, predicted MUC1-ED shedding in the same patient. Desialylated MUC1-ED was only detected in BALF of Pa-infected patients. Clinical Pa strains increased MUC1-ED shedding from cultured human alveolar epithelia, and FlaA and FlaB flagellin-expressing strains provoked comparable levels of MUC1-ED shedding. A flagellin-deficient isogenic mutant generated dramatically reduced MUC1-ED shedding compared with the flagellin-expressing wild-type strain, and purified FlaA and FlaB recapitulated the effect of intact bacteria. Pa:MUC1-ED complexes were detected in the supernatants of alveolar epithelia exposed to wild-type Pa, but not to the flagellin-deficient Pa strain. Finally, human recombinant MUC1-ED dose-dependently disrupted multiple flagellin-driven processes, including Pa motility, Pa biofilm formation, and Pa adhesion to human alveolar epithelia, while enhancing human neutrophil-mediated Pa phagocytosis. Therefore, shed desialylated MUC1-ED functions as a novel flagellin-targeting, Pa-responsive decoy receptor that participates in the host response to Pa at the airway epithelial surface.

Cross-talk between cancer and Pseudomonas aeruginosa mediates tumor suppression

“…3b ). It has been reported that MUC1, an O-glycosylated membrane-tethered mucin on cancer cells, interacts with P. aeruginosa through flagellin 44 , 45 . Muc1 ‒/‒ animals displayed ~50% less adherence of P. aeruginosa in the lungs compared with Muc1 +/+ mice 46 .…”

Mammalian Neuraminidases in Immune-Mediated Diseases: Mucins and Beyond

“…MUC1 expression also influences a variety of other human bacterial infections, including those by E. coli , S. enterica Typhimurium, S. pneumoniae , Staphylococcus aureus , Bacillus subtilis , Campylobacter jejuni , and Haemophilus influenzae ( 257 – 267 ). Based on these studies and the documented role of the NEU1 – MUC1 axis in regulating airway inflammation in response to P. aeruginosa ( 40 , 49 , 51 , 232 ), it is likely that this same pathway impacts the interaction of a broad array of pathogenic microorganisms with the human host. In summary, these collective studies suggest that NEUs and MUCs play important roles in regulating bacterial infections.…”

“…To extend these results to an in vivo human setting, studies were conducted to determine whether shed MUC1-ED levels might be elevated in BALF of patients with P. aeruginosa lung infection, and whether the recombinant MUC1-ED protein might influence in vitro parameters of the host proinflammatory response to bacterial infection ( 232 ). BALF from patients with P. aeruginosa pneumonia contained higher levels of MUC1-ED, compared with either BALF from noninfected patients or patients infected with microorganisms other than P. aeruginosa , and shed MUC1-ED in the BALF of P. aeruginosa -infected patients was desialylated, presumably from the action of NEU1.…”

The role of sialidase Neu1 in respiratory diseases

“…Subsequently, they also verified that Neu1 provoked the shedding of MUC1-ED from airway, which suppressed Pa lung infection in BALB/c mice [ 9 ]. Recently, Simeon’ team reported that the concentration of desialylated MUC1-ED and flagellin expression in Pa were dramatically increased in bronchoalveolar lavage fluid (BALF) harvested from Pa-infected patients [ 10 ], this indicated that measurement of MUC1-ED in BALF levels might serve as a guide for antibiotic therapy in patients with Pa-infections. In summary, different in vivo experiments confirmed that NEU1 might modulate the desialylation of human ECs receptors to resist the pulmonary bacterial infections.…”

“…Previously, much attention has been paid to the role of Neu1from viral and bacterial in human respiratory diseases. In recent years, there has been growing interest in the role of human Neuraminidases 1 (Neu1), a sialidase enzyme, in the development and progression of respiratory diseases [ 1 – 10 ].…”