Genetic variation in SP-A2 leads to differential binding to Mycoplasma pneumoniae membranes and regulation of host responses

• Published in: The Journal of immunology (1950) 2015-06, Vol.194 (12), p.6123-6132
• Main Authors: Ledford, Julie G, Voelker, Dennis R, Addison, Kenneth J, Wang, Ying, Nikam, Vinayak S, Degan, Simone, Kandasamy, Pitachaimani, Tanyaratsrisakul, Sasipa, Fischer, Bernard M, Kraft, Monica, Hollingsworth, John W
• Format: Article
• Language: English
• Subjects: Animals; Cell Membrane - immunology; Cell Membrane - metabolism; Chemotaxis - immunology; ErbB Receptors - metabolism; Female; Gene Expression; Gene Order; Gene Targeting; Genetic Variation; Genetic Vectors - genetics; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Humans; Lung - immunology; Lung - metabolism; Lung - microbiology; Lung - pathology; Male; Mice; Mice, Knockout; Mice, Transgenic; Mucin 5AC - genetics; Mucin 5AC - metabolism; Mucus - metabolism; Mycoplasma pneumoniae; Mycoplasma pneumoniae - immunology; Mycoplasma pneumoniae - metabolism; Neutrophils - immunology; Neutrophils - metabolism; Phosphorylation; Pneumonia, Mycoplasma - genetics; Pneumonia, Mycoplasma - immunology; Pneumonia, Mycoplasma - metabolism; Protein Binding; Pulmonary Surfactant-Associated Protein A - genetics; Pulmonary Surfactant-Associated Protein A - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1500104

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.