title: Genetic variation in SP-A2 leads to differential binding to Mycoplasma pneumoniae membranes and regulation of host responses.
abstract: Mycoplasma pneumoniae is an extracellular pathogen that colonizes mucosal surfaces of the respiratory tract and is associated with asthma exacerbations. Previous reports demonstrate that surfactant protein-A (SP-A) binds live M. pneumoniae and mycoplasma membrane fractions (MMF) with high affinity. Humans express a repertoire of single-amino acid genetic variants of SP-A that may be associated with lung disease, and our findings demonstrate that allelic differences in SP-A2 (Gln223Lys) affect the binding to MMF. We show that SP-A(-/-) mice are more susceptible to MMF exposure and have significant increases in mucin production and neutrophil recruitment. Novel humanized SP-A2-transgenic mice harboring the hSP-A2 223K allele exhibit reduced neutrophil influx and mucin production in the lungs when challenged with MMF compared with SP-A(-/-) mice. Conversely, mice expressing hSP-A2 223Q have increased neutrophil influx and mucin production that are similar to SP-A(-/-) mice. Using tracheal epithelial cell cultures, we show that enhanced mucin production to MMF occurs in the absence of SP-A and is not dependent upon neutrophil recruitment. Increased phosphorylation of the epidermal growth factor receptor (EGFR) was evident in the lungs of MMF-challenged mice when SP-A was absent. Pharmacologic inhibition of EGFR prior to MMF challenge dramatically reduced mucin production in SP-A(-/-) mice. These findings suggest a protective role for SP-A in limiting MMF-stimulated mucin production that occurs through interference with EGFR-mediated signaling. SP-A interaction with the EGFR signaling pathway appears to occur in an allele-specific manner that may have important implications for SP-A polymorphisms in human diseases.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710; Department of Medicine, University of Arizona, Tucson, AZ 85721; jledford@deptofmed.arizona.edu.
authors.forename: Julie G
authors.initials: JG
authors.lastname: Ledford
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO 80206;
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Voelker
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710; Department of Medicine, University of Arizona, Tucson, AZ 85721;
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Addison
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710; Department of Medicine, University of Arizona, Tucson, AZ 85721;
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710;
authors.forename: Vinayak S
authors.initials: VS
authors.lastname: Nikam
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, NC 27710;
authors.forename: Simone
authors.initials: S
authors.lastname: Degan
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO 80206;
authors.forename: Pitachaimani
authors.initials: P
authors.lastname: Kandasamy
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO 80206;
authors.forename: Sasipa
authors.initials: S
authors.lastname: Tanyaratsrisakul
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC 27710; and.
authors.forename: Bernard M
authors.initials: BM
authors.lastname: Fischer
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710; Department of Medicine, University of Arizona, Tucson, AZ 85721;
authors.forename: Monica
authors.initials: M
authors.lastname: Kraft
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710; Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210.
authors.forename: John W
authors.initials: JW
authors.lastname: Hollingsworth
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D018390:Gene Targeting; D014644:Genetic Variation; D005822:Genetic Vectors / Q000235:genetics; D054884:Host-Pathogen Interactions / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D009093:Mucus / Q000378:metabolism; D009177:Mycoplasma pneumoniae / Q000276:immunology* / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011019:Pneumonia, Mycoplasma / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics* / Q000378:metabolism
chemical_list: D055271:Mucin 5AC; D037662:Pulmonary Surfactant-Associated Protein A; C445843:SFTPA2 protein, human; D066246:ErbB Receptors