Staphylococcus aureus is a major human pathogen, associated with many types of infection including severe pneumonia. S. aureus activate multiple, often redundant proinflammatory signaling cascades in the lungs involving the airway epithelium as well as neutrophils, alveolar macrophages, dendritic cells and recruited T cells. While neutrophils are critical in the eradication of S. aureus, excessive proinflammatory signaling contributes to pulmonary damage. Our ongoing studies suggest that S. aureus directly activate na?ve CD4+ T cells through expression of multiple superantigens resulting in a hyperinflammatory response. Resident alveolar macrophages, through expression of cytokines such as IL-27 and co-inhibitory signals such as PD-L1, normally function to regulate T cell activation. In the experiments proposed we will establish how S. aureus induced necroptosis may limit the contribution of macrophage immunoregulatory molecules in T cell regulation and whether the macrophage-T cell interaction could be therapeutic target to improve the outcome of methicillin-resistant S. aureus (MRSA) pneumonia. This will be accomplished using wild type and knockout murine models of acute pneumonia, human PBMCs, alveolar macrophages and cell lines. Strategies to prevent T cell activation, by increasing macrophage numbers, blocking co-stimulatory proteins, or delivering exogenous co-inhibitory molecules will be evaluated for their efficacy in the setting of acute MRSA pneumonia. Given the limited efficacy of currently available antibiotics in the setting of MRSA infection, we postulate that enhancing normal immune clearance mechanisms could greatly benefit outcome.

Public Health Relevance

Staphylococcus aureus is a common human pathogen associated with multiple types of infection including pneumonia. Much of the pathology associated with methicillin-resistant S. aureus (MRSA) pneumonia is due to excessive inflammatory responses. In this project we will establish how alveolar macrophages regulate T cells in the setting of acute pneumonia and determine if macrophage function can be enhanced to prevent the pathological consequences of severe MRSA pneumonia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL079395-09A1
Application #
8766304
Study Section
Special Emphasis Panel (ZRG1-IDM-S (02))
Program Officer
Punturieri, Antonello
Project Start
2004-12-01
Project End
2018-06-30
Budget Start
2014-08-15
Budget End
2015-06-30
Support Year
9
Fiscal Year
2014
Total Cost
$396,162
Indirect Cost
$146,162
Name
Columbia University (N.Y.)
Department
Pediatrics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Parker, Dane; Planet, Paul J; Soong, Grace et al. (2014) Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains. PLoS Pathog 10:e1003951
Ahn, D S; Parker, D; Planet, P J et al. (2014) Secretion of IL-16 through TNFR1 and calpain-caspase signaling contributes to MRSA pneumonia. Mucosal Immunol 7:1366-74
Cohen, Taylor S; Prince, Alice S (2013) Bacterial pathogens activate a common inflammatory pathway through IFNýý regulation of PDCD4. PLoS Pathog 9:e1003682
Soong, Grace; Chun, Jarin; Parker, Dane et al. (2012) Staphylococcus aureus activation of caspase 1/calpain signaling mediates invasion through human keratinocytes. J Infect Dis 205:1571-9
Parker, Dane; Prince, Alice (2012) Immunopathogenesis of Staphylococcus aureus pulmonary infection. Semin Immunopathol 34:281-97
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
Soong, Grace; Martin, Francis J; Chun, Jarin et al. (2011) Staphylococcus aureus protein A mediates invasion across airway epithelial cells through activation of RhoA GTPase signaling and proteolytic activity. J Biol Chem 286:35891-8
Martin, Francis J; Parker, Dane; Harfenist, Bryan S et al. (2011) Participation of CD11c(+) leukocytes in methicillin-resistant Staphylococcus aureus clearance from the lung. Infect Immun 79:1898-904
Martin, Francis J; Gomez, Marisa I; Wetzel, Dawn M et al. (2009) Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A. J Clin Invest 119:1931-9

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