S. aureus activates TNF signaling pathways PROJECT SUMMARY Staphylococcus aureus remains a major cause of human infection and the prevalence of invasive staphylococcal disease has increased in the past few years. Protein A or SpA is a highly conserved surface component of S. aureus that has multiple interactions with the immune system. Discrete domains of SpA activate TNFa signaling, EGFR-mediating responses and the activation of the type I interferon cascade. The SpA IgG binding domain activates TNFR1, an interaction that is central to the pathogenesis of pneumonia. We postulate that the SpA-TNFRI interaction is critical in staphylococcal invasion across mucosal barriers through its activation of RhoA GTPases that perturb actomyosin dynamics and disrupt epithelial tight junctions. The SpA IgG binding domain also is an EGFR ligand, stimulating its phosphorylation and activating the ADAM17 metallo-protease. We predict that EGFR also mediates the internalization of SpA, which, through its Xr domain, activates the type I interferon cascade, inducing epithelial production of IFN-b and Jak-STAT phosphorylation in a TLR4/TRIF-dependent fashion. Staphylococcal activation of type I interferons via the TLR4 cascade is postulated to have a major role in the pathogenesis of pneumonia and sepsis. As the Xr domain is a common site of in vivo mutation, duplication and deletion, we will determine if these mutations selected in vivo are generated specifically in response to immune pressure and establish how polymorphisms in Xr contribute to the virulence of S. aureus.

Public Health Relevance

S. aureus activates TNF signaling pathways PROJECT NARRATIVE Staphylococcus aureus infection, especially MRSA infection, is a major public health problem causing increasing morbidity and mortality in previously healthy children and adults. This application focuses upon a major surface component of these bacteria, protein A, which has several important interactions with the immune responses of the host. We will establish the role of protein A in staphylococcal invasion across mucosal barriers as well as its ability to activate the type I interferon cascade in the lung. These studies will demonstrate how mutations in protein A have evolved to enhance the virulence of the organism and provide a potential target for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079395-07
Application #
8252149
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Banks-Schlegel, Susan P
Project Start
2004-12-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
7
Fiscal Year
2012
Total Cost
$395,998
Indirect Cost
$148,498
Name
Columbia University (N.Y.)
Department
Pediatrics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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:

Showing the most recent 10 out of 25 publications