In situ hybridization demonstrating the expression of human beta-defensin-1 mRNA in surface epithelia and submucosal gland epithelia of a bronchus from a patient with cystic fibrosis.

Pulmonary Host Defenses
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Despite the intimate contact between the lung and the external environment that occurs with each breath, the intrapulmonary airways are normally sterile and free of inflammation. A well-orchestrated innate immune system contributes to this remarkable state of affairs. We are broadly interested in host-pathogen interactions and epithelial responses to bacteria and viruses. Innate host defenses at the mucosal surfaces of the airways include the recognition of microbial patterns via the Toll-like family of receptors and the production of chemokines, cytokines, and antimicrobial proteins and peptides by epithelia. The lab is investigating the role of the epithelium in microbial pattern recognition and the down stream responses that are elicited when products such as Gram positive or negative bacterial cell wall componentsare sensed.

Studies of the microbicidal properties of the airway surface liquid have stimulated an interest in understanding the antimicrobial products secreted by epithelia. Antimicrobial proteins and peptides play important roles in the innate and adaptive mucosal immune responses of the lung and defects in their function may contribute to the pathogenesis of lung infections in cystic fibrosis. The production of these factors may be constitutive or inducible. We are using large scale microarray expression profiling to identify novel epithelial host defense genes. We are investigating the role of candidate antimicrobial proteins and peptides in airway defenses, including the beta-defensins, members of the lipid transfer/lipopolysaccharide binding protein family, and other novel proteins identified from expression profiling. A long term goal is to identify antimicrobial peptides/proteins that may have potential for drug development as topical antibiotics for the treatment or prevention of lung disease.

Tertiary structure of BNBD-12 and HBD-2 proteins. Ribbon representation of the lowest energy conformers for BNBD-12 (A) and HBD-2 (B) proteins. The structures shown are the first from the Protein Data Bank and were generated with the program Molecule Analysis and Molecule Display (MOLMOL) (197). The N- and C-termini are labeled. The three beta-sheets are indicated by blue ribbons and the disulfide bonds by yellow bars. Hydrophobicity map for the lowest energy conformers for the BNBD-12(C) and HBD-2 (D) proteins. The hydrophilic areas are shown in blue and the hydrophobic areas are shown in reddish brown (SYBYL 6.5, Tripos, Inc., St Louis, MO). The locations of key hydrophilic and hydrophobic residues are indicated for comparison between the primary sequence and each of the models in this figure.