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Combating Staph aureus superantigen toxins

Superantigen toxins : Of cytokine storms and immune short-circuits -how do we combat the ensuing system blackout ?

New research findings [1,2]  suggest that dangerous bacteria Staphylococcus aureus (S. aureus) are no longer able to interact and cause inflammation in target epithelial cells when CD40 specific molecules are genetically removed from these cells by CRISPR editing. These findings suggest immune activation and subsequent disease caused by S. aureus superantigen (SAgs) class of toxins may be prevented by blocking their interaction with human epithelial cells through CD40. It also points to the need for further research to investigate if other pathogens cause diseases through the same receptor interaction. Many other published reports by university and industry alike are now focused on the role of superantigens in S. aureus disease, signifying paradigm shift for R&D looking to find ways to combat these toxins.

Superantigens cause massive cytokine storms and disrupt the host immune system

S. aureus is a resilient, gram-positive pathogen that causes several infections in humans, including skin infections, pneumonia, food poisoning, toxic shock syndrome, blood poisoning and osteomyelitis. It uses a plethora of virulence factors to breach the host (human) defenses, including production of extracellular toxins to evade the human immune system and cause clinical disease. In contrast to conventional antigens that undergo proteolytic processing by antigen presenting cells and are presented as major histocompatibility complex (MHC)/peptide complex to T cells (immune cells), SAgs cross-link T cell receptor (TCR) with MHC Class II and activate up to 30% of T cells. This then causes a massive release of cytokines and chemokines, which in turn leads to enhanced expression and activation of cell-adhesion molecules, increased T-cell proliferation, and eventually T-cell apoptosis or T cell anergy. SAg-mediated immune activation is likely to be responsible for some of the characteristic symptoms associated with infections with SAg-producing microbes, such as the toxic shock syndrome (TSS) and food poisoning caused by staphylococci. The immune “short-circuit” caused by SAgs also is implicated in the virulence of S. aureus where along with other toxins it can lead to pneumonia, infective endocarditis, neonatal exanthematous disease, sepsis, and atopic dermatitis and total system shutdown.

Image borrowed from Kaempfer R. Bacterial superantigen toxins, CD28, and drug development. Toxins (Basel). (2018) 10:E459. doi: 10.3390/toxins10110459

Many recent publication though show promising progress to mounting a successfully defense against SAg associated disease [3] and for developing vaccine and therapeutics that will provide clinical protection against superantigen toxins [4]. The growing body of knowledge about superantigens such Staphylococcal enterotoxins (SE) – SEA, SEB and Toxic shock syndrome toxin (TSST-1)  will be the key to advancing towards the development rationally designed and successful attenuated antibacterial vaccines.

Related publications

  1. University of Iowa Health Care. “Different bacteria use same cell surface molecule to invade tissue and promote infection: Blocking bacteria-molecule interaction might prevent many deadly illnesses.” ScienceDaily, 19 March 2019. <https://www.sciencedaily.com/releases/2019/03/190319121748.htm>.
  2.  Patrick M. Schlievert, Michael P. Cahill, Bruce S. Hostager, Amanda J. Brosnahan, Aloysius J. Klingelhutz, Francoise A. Gourronc, Gail A. Bishop, Donald Y. M. Leung. “Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines.” mBio, 2019; 10 (2) doi:10.1128/mBio.00214-19
  3. Wilbur H Chen, Marcela F Pasetti, Rajan P. Adhikari, Holly Baughman, Robin Douglas, Jill El-Khorazaty, Nancy E. Greenberg, Frederick W. Holtsberg, Grant C. Liao, Mardi K. Reymann, Xiao-lin Wang, Kelly Lyn Warfield, M Javad Aman “Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax.” Clinical and vaccine immunology : CVI 23,12 918-925. 5 Dec. 2016, doi:10.1128/CVI.00399-16
  4. Arundhathi Venkatasubramaniam, Rajan P. Adhikari, Thomas Kort, Grant C. Liao, Shawn Conley, Laura Abaandou, Shweta Kailasan, Yoshikuni Onodera, Subramaniam Krishnan, Didier M. Djagbare, Frederick W. Holtsberg, Hatice Karauzum & M. Javad Aman. “TBA225, a fusion toxoid vaccine for protection and broad neutralization of staphylococcal superantigens.” Scientific Reports, volume 9, Article number: 3279 (2019), doi:10.1038/s41598-019-39890-z
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