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Most Spes are superantigens that cause excessive inflammation by activating large numbers of T cells. However, Streptococcal pyogenic exotoxin B (SpeB) is an exception, which is pro-inflammatory through its protease activity. Prior work shows that SpeB has the potential to cleave bacterial proteins. If cleavage of superantigens results in their inactivation, this gives the possibility that these two classes of exotoxins work at cross-purposes. We examined SpeB cleavage of the 11 major GAS superantigens and found that lability was not specific to structure, conservation, or, when compared to orthologous superantigens from\n              <jats:italic>Staphylococcus aureus<\/jats:italic>\n              , species of origin. We further show that rather than strictly antagonizing superantigen activity through degradation, SpeB can synergistically enhance superantigen-induced inflammation. For SpeB-labile superantigens, such as SmeZ, this is limited due to degradation, but for protease-resistant superantigens like SpeA, activity remains synergistic even at high protease concentrations. These findings suggest two modes by which proteases like SpeB may post-translationally regulate superantigens: positively, as a force amplifier that cooperatively increases inflammation, and negatively, through degradation that could act as a rheostat-like mechanism to limit excessive immune activation. Both mechanisms may contribute to the pathogenesis of GAS and other superantigen-producing pathogens.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>\n                <jats:bold>IMPORTANCE<\/jats:bold>\n              <\/jats:title>\n              <jats:p>\n                <jats:italic>Streptococcus pyogenes<\/jats:italic>\n                produces both superantigen and protease virulence factors to subvert host immunity. However, its major protease is highly promiscuous and would potentially limit superantigen activity through its degradation. We profile the sensitivity of the streptococcal superantigens to degradation by the protease SpeB, providing evidence that many are highly resistant. Furthermore, we show that these important toxins can have synergistic proinflammatory activity. This provides insight into diseases like scarlet fever and toxic shock syndrome caused by these toxins and suggests anti-inflammatories that may be therapeutically useful.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/iai.00405-24","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T14:04:13Z","timestamp":1738159453000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["Proinflammatory synergy between protease and superantigen streptococcal pyogenic exotoxins"],"prefix":"10.1128","volume":"93","author":[{"given":"Anders F.","family":"Johnson","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta, USA"]},{"name":"Microbiology and Molecular Genetics Graduate Program, Emory University","place":["Atlanta, 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