The biodefense agent Staphylococcus aureus enterotoxin is regarded as a superantigen (SAg) because it is not processed as conventional peptide and is an incredibly powerful T cell stimulant. Enterotoxins can cause lethal toxic shock in humans and intentional aerosol exposure of S. aureus enterotoxin has the potential to incapacitate large groups of people. The consequences of such a biological attack can lead to severe respiratory illness in exposed individuals. Notwithstanding, certain pulmonary diseases in human patients have recently been associated with the presence of SAg, and stimulation of T cells with SAg in the respiratory tract drives an inflammatory cascade resulting in severe pathological outcomes in the lung. This includes pulmonary inflammation, vascular permeability and alveolitis. Although this pathogenic response involves SAg-specific T cells, the underlying mechanism of disease initiation and mediators of lung inflammation are unclear. Our data show that innate cell recruitment and their activation in lung are dependent upon TCR Vp bearing T cells and occurs rapidly after exposure. A new finding clearly demonstrates this point since only a few hours after SAg inhalation y.ST cells begin to synthesize I L-17a. Unexpectedly, 1L-I7a production was shown to be dependent on the presence of TCR Vp T cells. The role of SAg-specific IT cell sub-populations involved in controlling Y 5 T cell activation will be investigated in Aim 1. A consequence of early innate cell activation is pulmonary tissue injury, and by proteomic mining of bronchoalveolar lavage fluid we detected intracellular proteins that may have come from damaged lung cells.
In Aim 2 we will purify and characterize a protease-sensitive factor that we detected in bronchoalveolar lavage fluid which has characteristics of a DAMP. Our goal is to identify this molecule and validate its ability to stimulate cytokine release by defining its cellular target and signaling properties. Lastly, an outcome of DAMP activity is intensification of inflammation, and in this regard our new data show a potential role for the IL-33 pathway.
Aim 3 will test how S. aureus enterotoxin inhalation impacts the IL-33 pathway and if it can be modulated to develop countermeasures against a pulmonary crisis.

Public Health Relevance

The study of enterotoxins released from Staphylococcus aureus is an important area of research due to the role these proteins play in inducing very strong immune responses. The nature ofthese proteins allows T cells to respondlvigorously which can lead to serious illness in people for which there is no clear treatment. This proposal will address important issues centered on understanding the initiation of these responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI056172-08A1
Application #
8424005
Study Section
Special Emphasis Panel (ZAI1-PA-I (S1))
Project Start
2003-09-01
Project End
2018-04-30
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
8
Fiscal Year
2013
Total Cost
$383,308
Indirect Cost
$112,983
Name
University of Connecticut
Department
Type
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Benoun, Joseph M; Peres, Newton G; Wang, Nancy et al. (2018) Optimal protection against Salmonella infection requires noncirculating memory. Proc Natl Acad Sci U S A 115:10416-10421
Ménoret, Antoine; Buturla, James A; Xu, Maria M et al. (2018) T cell-directed IL-17 production by lung granular ?? T cells is coordinated by a novel IL-2 and IL-1? circuit. Mucosal Immunol 11:1398-1407
Shinde, Paurvi; Liu, Wenhai; Ménoret, Antoine et al. (2017) Optimal CD4 T cell priming after LPS-based adjuvanticity with CD134 costimulation relies on CXCL9 production. J Leukoc Biol 102:57-69
Liu, Wenhai; Menoret, Antoine; Vella, Anthony T (2017) Responses to LPS boost effector CD8 T-cell accumulation outside of signals 1 and 2. Cell Mol Immunol 14:254-253
Lee, Seung-Joo; Benoun, Joseph; Sheridan, Brian S et al. (2017) Dual Immunization with SseB/Flagellin Provides Enhanced Protection against Salmonella Infection Mediated by Circulating Memory Cells. J Immunol 199:1353-1361
Romagnoli, P A; Fu, H H; Qiu, Z et al. (2017) Differentiation of distinct long-lived memory CD4 T cells in intestinal tissues after oral Listeria monocytogenes infection. Mucosal Immunol 10:520-530
Pham, Oanh H; O'Donnell, Hope; Al-Shamkhani, Aymen et al. (2017) T cell expression of IL-18R and DR3 is essential for non-cognate stimulation of Th1 cells and optimal clearance of intracellular bacteria. PLoS Pathog 13:e1006566
Risso, Gabriela S; Carabajal, Marianela V; Bruno, Laura A et al. (2017) U-Omp19 fromBrucella abortusIs a Useful Adjuvant for Vaccine Formulations againstSalmonellaInfection in Mice. Front Immunol 8:171
Svedova, Julia; Ménoret, Antoine; Mittal, Payal et al. (2017) Therapeutic blockade of CD54 attenuates pulmonary barrier damage in T cell-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 313:L177-L191
Benoun, Joseph M; Labuda, Jasmine C; McSorley, Stephen J (2016) Collateral Damage: Detrimental Effect of Antibiotics on the Development of Protective Immune Memory. MBio 7:

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