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.
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.
|Kitur, Kipyegon; Wachtel, Sarah; Brown, Armand et al. (2016) Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling. Cell Rep 16:2219-30|
|Parker, Dane; Prince, Alice (2016) Immunoregulatory effects of necroptosis in bacterial infections. Cytokine 88:274-275|
|Parker, Dane; Ahn, Danielle; Cohen, Taylor et al. (2016) Innate Immune Signaling Activated by MDR Bacteria in the Airway. Physiol Rev 96:19-53|
|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|
|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|
|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|
|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|
|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|
|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:|
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