The airway epithelium initiates defenses against inhaled pulmonary pathogens by signaling to recruit phagocytic cells to the site of infection. This signaling is accomplished by toll-like receptors that are activated by conserved bacterial components, stimulate MAPKs and NF-?B signaling cascades to elicit expression of chemokines such as IL-8 that recruit PMNs into the airway. For PMNs to transmigrate across the tight junctions of the epithelial barrier, several membrane spanning proteins of the tight and adherens junctions must be modified. We propose that TLR signaling initiated by TLR2 and possibly TLR5 activates the Ca2+ dependent protease calpain, which targets the epithelial junctional proteins occludin and E-cadherin to facilitate paracellular passage of PMNs into the airway. Similarly, LPS activation of TLR4 induces cleavage of junctional proteins by Ca2+-independent proteases, such as TACE to facilitate PMN transmigration. These same junctional components are also the targets of bacterial virulence factors, the type III secreted toxins of P. aeruginosa, which further modify the epithelial barrier to facilitate bacterial invasion. The combined effects of GTPase inhibition and ADP ribosylation, the activities of P. aeruginosa toxins, alters the localization and functions of junctional proteins critical for the maintenance of the epithelial cytoskeleton and its barrier function. In the experiments proposed we will characterize the signaling process that facilitates PMN migration through the epithelial barrier and how the same targets can be exploited by bacterial pathogens.
Calcium dependent signaling in airway epithelial cells Pneumonia, the accumulation of inflammatory cells in the lung, is a major cause of morbidity and mortality. This project seeks to understand the fundamental process through which polymorphonuclear leukocytes are recruited into the airway in response to bacterial infection.
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|Cohen, Taylor S; Prince, Alice S (2013) Bacterial pathogens activate a common inflammatory pathway through IFNýý regulation of PDCD4. PLoS Pathog 9:e1003682|
|Cohen, Taylor S; Prince, Alice S (2013) Activation of inflammasome signaling mediates pathology of acute P. aeruginosa pneumonia. J Clin Invest 123:1630-7|
|Parker, Dane; Prince, Alice (2013) Epithelial uptake of flagella initiates proinflammatory signaling. PLoS One 8:e59932|
|Parker, Dane; Cohen, Taylor S; Alhede, Morten et al. (2012) Induction of type I interferon signaling by Pseudomonas aeruginosa is diminished in cystic fibrosis epithelial cells. Am J Respir Cell Mol Biol 46:6-13|
|Cohen, Taylor Sitarik; Prince, Alice (2012) Cystic fibrosis: a mucosal immunodeficiency syndrome. Nat Med 18:509-19|
|Parker, Dane; Prince, Alice (2011) Innate immunity in the respiratory epithelium. Am J Respir Cell Mol Biol 45:189-201|
|Pier, Gerald; Prince, Alice; Cantin, Andre (2011) Cystic fibrosis: an-ion transport issue? Nat Med 17:166-7|
|Chun, Jarin; Prince, Alice (2009) TLR2-induced calpain cleavage of epithelial junctional proteins facilitates leukocyte transmigration. Cell Host Microbe 5:47-58|
|Martin, Francis J; Prince, Alice S (2008) TLR2 regulates gap junction intercellular communication in airway cells. J Immunol 180:4986-93|
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