The long-term goals are characterization of superantigens (SAgs) causation of diseases. SAgs cause toxic shock syndrome (TSS). However, it is our hypothesis that SAgs contribute to other illnesses. We theorize SAgs produced by emerging strains of methicillin resistant Staphylococcus aureus (MRSA) (USA 200, 300, and 400) contribute to necrotizing pneumonia (NP), pulmonary TSS, and endocarditis. We also hypothesize there may be adjuvant uses for SAgs, when toxicity is eliminated. We plan two specific aims:
Aim 1 : To characterize adjuvant activities of non-lethal SAg toxoids that amplify antibody production when administered intravenously or mucosally, as a consequence of their abilities to interact with CD40. We provide evidence that SAgs contain a domain that facilitates mucosal penetration, independent of superantigenicity, and that amplifies immune responses;both activities result from interaction with the immune co-stimulatory molecule CD40.
Specific aim 1 a. To prepare mutants in the dodecapeptide domain of SAgs, TSS toxin-1 and streptococcal pyrogenic exotoxin C, that lack CD40 binding.
Specific aim 1 b. To test wild-type SAgs and non-lethal mutants for ability to bind CD40 in immunoblots and Biacore analysis.
Specific aim 1 c. To test wild-type SAgs and dodecapeptide mutants for ability to penetrate porcine and rabbit vaginal mucosa.
Specific aim 1 d. To test non-lethal SAg mutants that retain mucosal penetration and CD40 binding for adjuvanticity, with the hypothesis that both activities result from mutant SAg interaction with CD40 on epithelial cells and APCs.
Aim 2 : To elucidate the contribution of staphylococcal SAgs to NP, pulmonary TSS, and endocarditis caused by emerging MRSA. We hypothesize that MRSA strains make higher levels of SAgs than MSSA strains, and that regulatory DNA controlling SAg production in MRSA is altered compared to MSSA. We also hypothesize that MRSA strains make high levels of SAgs required for NP, pulmonary TSS, and endocarditis, that alpha- hemolysin and Panton-Valentine leukocidin contribute to infections, but neither is required, and that SAgs contribute to infections by delaying antibody responses. These will be tested by use of isogenic strains, through vaccination, and by monitoring host responses.
Specific aim 2 a. In vitro characterization of emerging MRSA strains.
Specific aim 2 b. In vivo characterization of SAg contribution to CA-MRSA pulmonary infections.
Specific aim 2 c. Characterization of SAg contribution to MRSA endocarditis.
| Breshears, Laura M; Peterson, Marnie L (2016) Protocol for Examining Human Vaginal Epithelial Cell Signaling in Response to Staphylococcal Superantigens. Methods Mol Biol 1396:149-158 |
| Spaulding, Adam R; Salgado-Pabón, Wilmara; Merriman, Joseph A et al. (2014) Vaccination against Staphylococcus aureus pneumonia. J Infect Dis 209:1955-62 |
| Vu, Bao G; Stach, Christopher S; Salgado-Pabón, Wilmara et al. (2014) Superantigens of Staphylococcus aureus from patients with diabetic foot ulcers. J Infect Dis 210:1920-7 |
| Merriman, Joseph A; Nemeth, Kimberly A; Schlievert, Patrick M (2014) Novel antimicrobial peptides that inhibit gram positive bacterial exotoxin synthesis. PLoS One 9:e95661 |
| Stach, Christopher S; Herrera, Alfa; Schlievert, Patrick M (2014) Staphylococcal superantigens interact with multiple host receptors to cause serious diseases. Immunol Res 59:177-81 |
| Salgado-Pabón, Wilmara; Breshears, Laura; Spaulding, Adam R et al. (2013) Superantigens are critical for Staphylococcus aureus Infective endocarditis, sepsis, and acute kidney injury. MBio 4: |
| Spaulding, Adam R; Salgado-Pabón, Wilmara; Kohler, Petra L et al. (2013) Staphylococcal and streptococcal superantigen exotoxins. Clin Microbiol Rev 26:422-47 |
| Brosnahan, Amanda J; Merriman, Joseph A; Salgado-Pabon, Wilmara et al. (2013) Enterococcus faecalis inhibits superantigen toxic shock syndrome toxin-1-induced interleukin-8 from human vaginal epithelial cells through tetramic acids. PLoS One 8:e61255 |
| Pereira, Nigel; Edlind, Thomas D; Schlievert, Patrick M et al. (2013) Vaginal toxic shock reaction triggering desquamative inflammatory vaginitis. J Low Genit Tract Dis 17:88-91 |
| Vu, Bao G; Gourronc, Francoise A; Bernlohr, David A et al. (2013) Staphylococcal superantigens stimulate immortalized human adipocytes to produce chemokines. PLoS One 8:e77988 |
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