Dr. Erik Lillehoj
http://hdl.handle.net/10713/8292
2024-03-28T13:38:09ZDesialylated Host-Derived MUC1 Ectodomain and Bacterially-Derived Flagellin are Biomarkers for Airway Colonization and Infection with Pseudomonas aeruginosa in Mechanically Ventilated and Cystic Fibrosis Patients
http://hdl.handle.net/10713/18804
Desialylated Host-Derived MUC1 Ectodomain and Bacterially-Derived Flagellin are Biomarkers for Airway Colonization and Infection with Pseudomonas aeruginosa in Mechanically Ventilated and Cystic Fibrosis Patients
Verceles, Avelino C.; Bhat, Pavan; Nagaria, Zain; Martin, Destiny; Patel, Harsh; Ntem-Mensah, Afua; Hyun, Sang Won; Hahn, Andrea; Jeudy, Jean; Goldblum, Simeon E.; Lillehoj, Erik P.; Cross, Alan S.
Presented at the 13th annual NIH & FDA-wide Glycosciences Research Day on Friday, May 15, 2020, in the Natcher Conference Center, National Institute of Health Bethesda, Maryland.
2020-05-01T00:00:00ZNeuraminidase-1 Desialylates the MUC1 Ectodomain to Release a Decoy Receptor that Protects against Lethal Pseudomonas aeruginosa Lung Infection
http://hdl.handle.net/10713/12146
Neuraminidase-1 Desialylates the MUC1 Ectodomain to Release a Decoy Receptor that Protects against Lethal Pseudomonas aeruginosa Lung Infection
Lillehoj, Erik P.; Guang, Wei; Hyun, Sang Won
Background: Pseudomonas aeruginosa (Pa) is a major
opportunistic pathogen of human airways, but the host response to
infection is incompletely understood. Epithelial cells lining the
airways express numerous surface receptors that recognize
infectious agents such as Pa. One such receptor, MUC1, recognizes
Pa flagellin, the major structural protein of the bacterial flagellum.
MUC1 consists of an NH2-terminal, highly O-glycosylated
ectodomain (MUC1-ED) attached to the cell surface through a
membrane-spanning domain. MUC1-ED is proteolytically processed
and shed from the epithelial cell surface following cleavage at a
juxtamembranous Gly-Ser peptide bond. We previously
demonstrated that stimulation of human airway epithelial cells with
Pa flagellin increased MUC1-ED shedding in vitro (Lillehoj et al., J.
Biol. Chem. 290:18316, 2015). Using an intact, physiologically
relevant murine model of Pa pneumonia, here we asked whether Pa
and its flagellin might also stimulate NEU1-dependent MUC1-ED
desialylation in vivo to release a hyperadhesive decoy receptor that
provides a novel, protective host response to Pa lung infection.
Results: Intranasal administration of e5.0x103 colony forming units
of Pa strain K (PAK) to BALB/c mice increased MUC1-ED shedding
into the bronchoalveolar compartment. MUC1-ED levels increased
as early as 12 h, peaked at 24-48 h, reaching up to 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 isogenic PAK mutant provoked dramatically reduced
MUC1-ED shedding compared with the wild-type strain, and purified
flagellin recapitulated the wild-type effect. In lung tissues, Pa
increased MUC1-ED desialylation by peanut agglutinin lectin
blotting. NEU1-selective sialidase inhibition with C9-BA-DANA, or
use of a catalytically-inactive NEU1-G68V mutant, protected against
Pa-induced MUC1-ED desialylation and shedding. MUC1-ED
inhibition of in vitro Pa adhesion and flagellin binding to airway
epithelial cells was localized to its protein backbone and not to its
glycans. Finally, co-administration of Pa with human recombinant
(r)MUC1-ED expressed in E. coli diminished lung and BALF
bacterial burden, proinflammatory cytokine levels, and pulmonary
leukostasis, and enhanced 5-day survival from 0% to 75%.
Conclusions: These combined data indicate that Pa flagellin
provokes NEU1-mediated airway shedding of MUC1-ED as a decoy
receptor that protects against lethal Pa lung infection. Human
rMUC1-ED might someday be harnessed as a therapeutic
intervention to target Pa lung infections, including those associated
with multi-drug resistant organisms.
2020-01-01T00:00:00ZNEU1 Sialidase Associates with the MUC1 Cytoplasmic Domain and not the MUC1 Ectodomain
http://hdl.handle.net/10713/12140
NEU1 Sialidase Associates with the MUC1 Cytoplasmic Domain and not the MUC1 Ectodomain
Lillehoj, Erik P.; Hyun, Sang Won; Piepenbrink, Kurt H.; Guang, Wei; Goldblum, Simeon E.
Deglycosylated MUC1 Ectodomain for the Diagnosis and Treatment of Pseudomonas aeruginosa Lung Infections
http://hdl.handle.net/10713/8333
Deglycosylated MUC1 Ectodomain for the Diagnosis and Treatment of Pseudomonas aeruginosa Lung Infections
Lillehoj, Erik P.; Verceles, Avelino C.; Guang, Wei; Hyun, Sang Won; Liu, Anguo; Goldblum, Simeon E.
Poster presented at the 2016 NIH FDA Glycoscience Research Day in Bethesda, Maryland
2016-01-01T00:00:00Z