Bacterial superantigens (SAg) are exotoxins that trigger an excessive immune response that may lead to lethal shock. Because of their ability to induce incapacitation at exceedingly low concentrations and to elicit shock, their ease of production and their exceptional stability, SAgs are classified as Category B biological weapons. Attempts to reverse the deleterious effects of SAg intoxication by blocking downstream effectors such as TNF-a have failed owing to the massive levels induced. We prepared peptide mimetics of the contact domains in the SAg and a novel SAg receptor essential for the induction of Th1 cytokines which prevent lethal shock in a D-galactosamine (D-GalN)-sensitized mouse model of SEB as well as incapacitation in pigs. Since co-exposure of SAg with Gram-negative bacterial endotoxin (LPS) may be more clinically relevant, this proposal will test the hypothesis that antagonist peptides can prevent SAg/LPS svnergistic lethality and rescue exposed animals, while preserving adaptive immune responses.
In Specific Aim I we will determine whether antagonist peptides protect and rescue mice from LPS/SAg lethal synergy. Exposure to SAg and gut-derived LPS likely mimics the clinical situation, and the mechanism of SAg-induced pathology differs from that which occurs with D-GaIN sensitization.
In Specific Aim II, we will define the mechanism of antagonist peptide-mediated protection, show that it is broad-spectrum against SAgs, and assess whether peptide antagonists impair responses to immune stimulation with antigens or host defenses against live infection. IgG purified from the serum of mice challenged with SAg in the presence of peptide antagonist will be.tested by ELISA against peptides from different domains of SAg. These studies will be followed by cross-inhibition ELISA studies to identify IgG levels specific for SAg conserved epitopes. Since recent studies suggest that SAgs may alter APC function, in Specific Aim III we will analyze whether peptide antagonists (1) inhibit SAg effects on human monocytes, particularly Toll-like receptor expression and cytokine induction or (2) impair the ability of human dendritic cells to present B. anthracis antigens to T lymphocytes. These studies will further define a new mechanism of SAg signaling and the efficacy and safety of a novel therapeutic intervention against multiple SAgs. If we are successful, these peptide mimetics could soon be ready for phase I testing.

Public Health Relevance

Exposure to superantigens (SAgs) can cause lethal shock, particularly when it occurs in the presence of Gram-negative bacterial lipopolysaccharide (LPS). Efforts to decrease the massive cytokine release have either failed or led to prolonged T cell anergy. The use of peptide antagonists will be a useful, broad-based therapeutic against a wide range of SAgs that may be deployed in a bioterrorist attack, even when given up to 7 hrs after exposure.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
United States
Zip Code
Freedman, John C; Theoret, James R; Wisniewski, Jessica A et al. (2015) Clostridium perfringens type A-E toxin plasmids. Res Microbiol 166:264-79
Li, Jihong; McClane, Bruce A (2014) Contributions of NanI sialidase to Caco-2 cell adherence by Clostridium perfringens type A and C strains causing human intestinal disease. Infect Immun 82:4620-30
Moy, Ryan H; Gold, Beth; Molleston, Jerome M et al. (2014) Antiviral autophagy restrictsRift Valley fever virus infection and is conserved from flies to mammals. Immunity 40:51-65
Cuevas, Christian D; Ross, Susan R (2014) Toll-like receptor 2-mediated innate immune responses against Junín virus in mice lead to antiviral adaptive immune responses during systemic infection and do not affect viral replication in the brain. J Virol 88:7703-14
Boyd, Mary Adetinuke; Tennant, Sharon M; Saague, Venant A et al. (2014) Serum bactericidal assays to evaluate typhoidal and nontyphoidal Salmonella vaccines. Clin Vaccine Immunol 21:712-21
Su, Yi-Hsuan; Tsegaye, Mikiyas; Varhue, Walter et al. (2014) Quantitative dielectrophoretic tracking for characterization and separation of persistent subpopulations of Cryptosporidium parvum. Analyst 139:66-73
Xu, Jie; Cherry, Sara (2014) Viruses and antiviral immunity in Drosophila. Dev Comp Immunol 42:67-84
Uzal, Francisco A; Freedman, John C; Shrestha, Archana et al. (2014) Towards an understanding of the role of Clostridium perfringens toxins in human and animal disease. Future Microbiol 9:361-77
Weir, Dawn L; Laing, Eric D; Smith, Ina L et al. (2014) Host cell virus entry mediated by Australian bat lyssavirus G envelope glycoprotein occurs through a clathrin-mediated endocytic pathway that requires actin and Rab5. Virol J 11:40
Weir, Dawn L; Annand, Edward J; Reid, Peter A et al. (2014) Recent observations on Australian bat lyssavirus tropism and viral entry. Viruses 6:909-26

Showing the most recent 10 out of 299 publications