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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073989-06
Application #
7791378
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2003-09-01
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
6
Fiscal Year
2010
Total Cost
$402,063
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pediatrics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Ahn, Danielle; Prince, Alice (2017) Participation of Necroptosis in the Host Response to Acute Bacterial Pneumonia. J Innate Immun 9:262-270
Parker, Dane; Ahn, Danielle; Cohen, Taylor et al. (2016) Innate Immune Signaling Activated by MDR Bacteria in the Airway. Physiol Rev 96:19-53
Parker, Dane; Prince, Alice (2016) Immunoregulatory effects of necroptosis in bacterial infections. Cytokine 88:274-275
Ahn, Danielle; Peñaloza, Hernán; Wang, Zheng et al. (2016) Acquired resistance to innate immune clearance promotes Klebsiella pneumoniae ST258 pulmonary infection. JCI Insight 1:e89704
Westphalen, Kristin; Gusarova, Galina A; Islam, Mohammad N et al. (2014) Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity. Nature 506:503-6
Cohen, Taylor S; Prince, Alice S (2013) Bacterial pathogens activate a common inflammatory pathway through IFN? 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
Prince, Alice (2012) The bitter taste of infection. J Clin Invest 122:3847-9

Showing the most recent 10 out of 21 publications