application): Inflammation of the airway epithelium is often required for effective innate defense against microbes, and epithelial cells provide critical biochemical signals that regulate this response. One major mechanism that epithelial cells in the airway use to participate in the inflammatory response is through regulation of leukocyte trafficking and/or activation by expression of intercellular adhesion molecule-1 (ICAM-1). ICAM-1 serves as a ligand for leukocyte beta2-integrins and thereby mediates epithelial-leukocyte interactions that may allow for """"""""appropriate"""""""" inflammatory responses (e.g., to a respiratory bacterial infection) or """"""""inappropriate"""""""" responses (e.g., airway inflammation in cystic fibrosis). This proposal focuses on Haemophilus influenzae, which frequently colonizes human respiratory mucosa and often produces respiratory tract disease, particularly in patients with chronic bronchitis, bronchiectasis, and cystic fibrosis.
The specific aims of this proposal are based on four observations regarding airway epithelial cell ICAM-1 expression in response to H. influenzae: 1) H. influenzae induces airway epithelial cell ICAM-1 expression in vivo and in vitro; 2) ICAM-1 expression is required for efficient bacterial clearance in a murine model of airway infection with H. influenzae; 3) increased ICAM-1 expression can be initiated by epithelial cell interaction with a constitutive molecule on the bacterial cell surface; and 4) airway epithelial cell interaction with H. influezae results in generation of soluble ICAM-1 inducing activity containing a novel mediator(s) of ICAM-1 expression. Based on these observations, they hypothesize that direct induction of specific epithelial genes (such as ICAM-l) allow for rapid targeting and/or activation of neutrophils and other leukocytes at sites of H. influenzae infection, resulting in efficient innate defense in the airway. Accordingly, there are two specific aims. 1) Define mechanisms for induction of epithelial cell ICAM-1 expression by H. influenzae.
This aim will take advantage of in vitro coculture models of epithelial cell interaction with bacteria. Definition of mechanisms for ICAM-1 gene activation in response to H influenzae will be accomplished by analysis of ICAM-1 promoter function and identification of mediator molecules. This latter refers to the observation that airway epithelial cells challenged with H. influenzae release a novel soluble factor into the medium capable of eliciting ICAM-1 in naive epithelial cells. 2) Determine functions of ICAM-1 in defense against H. influenzae infection.
This aim will take advantage of in vivo murine models of airway infection by bacteria. The functions of ICAM-1 will be determined by examining ICAM-1 expression, leukocyte recruitment and function, and bacteria clearance under conditions that allow for manipulation of airway defense factors.
| Manzel, Lori J; Chin, Cecilia L; Behlke, Mark A et al. (2009) Regulation of bacteria-induced intercellular adhesion molecule-1 by CCAAT/enhancer binding proteins. Am J Respir Cell Mol Biol 40:200-10 |
| Look, Dwight C; Chin, Cecilia L; Manzel, Lori J et al. (2006) Modulation of airway inflammation by Haemophilus influenzae isolates associated with chronic obstructive pulmonary disease exacerbation. Proc Am Thorac Soc 3:482-3 |
| Humlicek, Alicia L; Pang, Liyi; Look, Dwight C (2004) Modulation of airway inflammation and bacterial clearance by epithelial cell ICAM-1. Am J Physiol Lung Cell Mol Physiol 287:L598-607 |
