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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IDM-S (02))
Program Officer
Punturieri, Antonello
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
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
Kitur, Kipyegon; Wachtel, Sarah; Brown, Armand et al. (2016) Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling. Cell Rep 16:2219-2230
Planet, Paul J; Parker, Dane; Cohen, Taylor S et al. (2016) Lambda Interferon Restructures the Nasal Microbiome and Increases Susceptibility to Staphylococcus aureus Superinfection. MBio 7:e01939-15
Kitur, Kipyegon; Parker, Dane; Nieto, Pamela et al. (2015) Toxin-induced necroptosis is a major mechanism of Staphylococcus aureus lung damage. PLoS Pathog 11:e1004820
Parker, Dane; Ryan, Chanelle L; Alonzo 3rd, Francis et al. (2015) CD4+ T cells promote the pathogenesis of Staphylococcus aureus pneumonia. J Infect Dis 211:835-45
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
Parker, Dane; Narechania, Apurva; Sebra, Robert et al. (2014) Genome Sequence of Bacterial Interference Strain Staphylococcus aureus 502A. Genome Announc 2:
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

Showing the most recent 10 out of 26 publications