{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:54:56Z","timestamp":1787032496585,"version":"build-2736575974"},"posted":{"date-parts":[[2026,5,15]]},"group-title":"Microbiology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Streptococcus pyogenes<\/jats:italic>\n                  (Group A\n                  <jats:italic>Streptococcus<\/jats:italic>\n                  ) causes infections with a disproportionately hyperinflammatory response from the host, such as scarlet fever, necrotizing fasciitis, and toxic shock syndrome. Inflammation is specifically driven by\n                  <jats:italic>S. pyogenes<\/jats:italic>\n                  virulence factors, including the protease SpeB, but how inflammation impacts SpeB expression in return during disease is unknown. In this study, we identify a novel interaction between NETosis, a form of inflammatory cell death for neutrophils, and the induction of\n                  <jats:italic>speB<\/jats:italic>\n                  . Specifically, while the cathelicidin peptide LL-37 can repress\n                  <jats:italic>speB<\/jats:italic>\n                  through the two-component regulatory system CovRS, neutrophil proteases released during NETosis relieve repression of\n                  <jats:italic>speB<\/jats:italic>\n                  by degrading another repressor of\n                  <jats:italic>speB<\/jats:italic>\n                  , the bacterial protein Vfr. Furthermore, at high cell densities, SpeB autoregulates its expression through similar degradation of Vfr. Abrogating the formation of NETs or depleting neutrophils resulted in\n                  <jats:italic>speB<\/jats:italic>\n                  repression\n                  <jats:italic>in vivo<\/jats:italic>\n                  , showing the mutual host and pathogen counterattacks collectively lead to the pathological exacerbations characteristic of disease.\n                <\/jats:p>","DOI":"10.64898\/2026.05.15.725401","type":"posted-content","created":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T04:00:21Z","timestamp":1778904021000},"source":"Crossref","is-referenced-by-count":1,"title":["A protease-sensing circuit links neutrophil inflammation to virulence regulation in\n                  <i>Streptococcus pyogenes<\/i>"],"prefix":"10.64898","author":[{"given":"Stephanie","family":"Guerra","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA"},{"name":"Microbiology and Molecular Genetics Program, Laney Graduate School, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ananya","family":"Dash","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA"},{"name":"Immunology and Molecular Pathogenesis Program, Laney Graduate School, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doris L.","family":"LaRock","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3035-5331","authenticated-orcid":false,"given":"Christopher N.","family":"LaRock","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA"},{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026051908401339000_2026.05.15.725401v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(05)70267-X"},{"key":"2026051908401339000_2026.05.15.725401v1.2","doi-asserted-by":"crossref","unstructured":"Misiakos, E. P. et al. Current Concepts in the Management of Necrotizing Fasciitis. Front. Surg. 1, (2014).","DOI":"10.3389\/fsurg.2014.00036"},{"key":"2026051908401339000_2026.05.15.725401v1.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0803815105"},{"key":"2026051908401339000_2026.05.15.725401v1.4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002361"},{"key":"2026051908401339000_2026.05.15.725401v1.5","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00394-12"},{"key":"2026051908401339000_2026.05.15.725401v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-023-00865-7"},{"key":"2026051908401339000_2026.05.15.725401v1.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2011.07709.x"},{"key":"2026051908401339000_2026.05.15.725401v1.8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000832"},{"key":"2026051908401339000_2026.05.15.725401v1.9","doi-asserted-by":"crossref","unstructured":"Ikebe, T. et al. Spontaneous mutations in Streptococcus pyogenes isolates from streptococcal toxic shock syndrome patients play roles in virulence. Sci. Rep. 6, 28761 (2016).","DOI":"10.1038\/srep28761"},{"key":"2026051908401339000_2026.05.15.725401v1.10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.202353699"},{"key":"2026051908401339000_2026.05.15.725401v1.11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05818.x"},{"key":"2026051908401339000_2026.05.15.725401v1.12","first-page":"e01642","article-title":"Identification of Group A Streptococcus Genes Directly Regulated by CsrRS and Novel Intermediate Regulators","volume":"12","year":"2021","journal-title":"mBio"},{"key":"2026051908401339000_2026.05.15.725401v1.13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302005"},{"key":"2026051908401339000_2026.05.15.725401v1.14","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1747.2001.01340.x"},{"key":"2026051908401339000_2026.05.15.725401v1.15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30142"},{"key":"2026051908401339000_2026.05.15.725401v1.16","doi-asserted-by":"publisher","DOI":"10.1128\/JB.185.17.5166-5174.2003"},{"key":"2026051908401339000_2026.05.15.725401v1.17","doi-asserted-by":"crossref","unstructured":"Do, H. et al. Leaderless secreted peptide signaling molecule alters global gene expression and increases virulence of a human bacterial pathogen. Proc. Natl. Acad. Sci. 114, (2017).","DOI":"10.1073\/pnas.1705972114"},{"key":"2026051908401339000_2026.05.15.725401v1.18","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01771-08"},{"key":"2026051908401339000_2026.05.15.725401v1.19","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2011.07902.x"},{"key":"2026051908401339000_2026.05.15.725401v1.20","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1016\/j.bbamem.2015.02.010","article-title":"Cationic antimicrobial peptide resistance mechanisms of streptococcal pathogens","volume":"1848","year":"2015","journal-title":"Biochim. Biophys. Acta BBA - Biomembr"},{"key":"2026051908401339000_2026.05.15.725401v1.21","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1998.00800.x"},{"key":"2026051908401339000_2026.05.15.725401v1.22","doi-asserted-by":"crossref","unstructured":"Bl\u00f6chl, C. et al. Proteolytic Profiling of Streptococcal Pyrogenic Exotoxin B (SpeB) by Complementary HPLC-MS Approaches. Int. J. Mol. Sci. 23, 412 (2021).","DOI":"10.3390\/ijms23010412"},{"key":"2026051908401339000_2026.05.15.725401v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21533-5"},{"key":"2026051908401339000_2026.05.15.725401v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00057-1"},{"key":"2026051908401339000_2026.05.15.725401v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-60306-w"},{"key":"2026051908401339000_2026.05.15.725401v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.12.039"},{"key":"2026051908401339000_2026.05.15.725401v1.27","doi-asserted-by":"publisher","DOI":"10.1160\/TH05-08-0572"},{"key":"2026051908401339000_2026.05.15.725401v1.28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075141"},{"key":"2026051908401339000_2026.05.15.725401v1.29","first-page":"e00356","article-title":"Group A Streptococcus Infection of the Nasopharynx Requires Proinflammatory Signaling through the Interleukin-1 Receptor","volume":"88","year":"2020","journal-title":"Infect. Immun"},{"key":"2026051908401339000_2026.05.15.725401v1.30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022043"},{"key":"2026051908401339000_2026.05.15.725401v1.31","doi-asserted-by":"crossref","unstructured":"Guerra, S. & LaRock, C . Group A Streptococcus interactions with the host across time and space. Curr. Opin. Microbiol. 77, 102420 (2024).","DOI":"10.1016\/j.mib.2023.102420"},{"key":"2026051908401339000_2026.05.15.725401v1.32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004155"},{"key":"2026051908401339000_2026.05.15.725401v1.33","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/s41564-023-01583-9","article-title":"Engineered probiotic overcomes pathogen defences using signal interference and antibiotic production to treat infection in mice","volume":"9","year":"2024","journal-title":"Nat. Microbiol"},{"key":"2026051908401339000_2026.05.15.725401v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/S1286-4579(02)01654-4"},{"key":"2026051908401339000_2026.05.15.725401v1.35","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2003.03797.x"},{"key":"2026051908401339000_2026.05.15.725401v1.36","unstructured":"Kansal, R. G. , Nizet, V. , Jeng, A. , Chuang, W.-J. & Kotb, M. Selective Modulation of Superantigen-Ind Responses by Streptococcal Cysteine Prot."},{"key":"2026051908401339000_2026.05.15.725401v1.37","doi-asserted-by":"publisher","DOI":"10.1159\/000203645"},{"key":"2026051908401339000_2026.05.15.725401v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04717-x"},{"key":"2026051908401339000_2026.05.15.725401v1.39","first-page":"e00840","article-title":"An efficient in vivo-inducible CRISPR interference system for group A Streptococcus genetic analysis and pathogenesis studies","volume":"15","year":"2024","journal-title":"mBio"},{"key":"2026051908401339000_2026.05.15.725401v1.40","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/978-1-59745-196-3_6","article-title":"The Polymerase Incomplete Primer Extension (PIPE) Method Applied to High-Throughput Cloning and Site-Directed Mutagenesis","volume":"498","year":"2009","journal-title":"in High Throughput Protein Expression and Purification (ed. Doyle, S. A.)"},{"key":"2026051908401339000_2026.05.15.725401v1.41","doi-asserted-by":"publisher","DOI":"10.1128\/JB.185.4.1208-1217.2003"},{"key":"2026051908401339000_2026.05.15.725401v1.42","first-page":"e00258","article-title":"Detoxification of reactive oxygen species by the hyaluronic acid capsule of group A Streptococcus","volume":"91","year":"2023","journal-title":"Infect. Immun"},{"key":"2026051908401339000_2026.05.15.725401v1.43","doi-asserted-by":"crossref","unstructured":"LaRock, C. N. et al. IL-1\u03b2 is an innate immune sensor of microbial proteolysis. Sci. Immunol. 1, (2016).","DOI":"10.1126\/sciimmunol.aah3539"},{"key":"2026051908401339000_2026.05.15.725401v1.44","first-page":"e00405","article-title":"Proinflammatory synergy between protease and superantigen streptococcal pyogenic exotoxins","volume":"93","year":"2025","journal-title":"Infect. Immun"},{"key":"2026051908401339000_2026.05.15.725401v1.45","doi-asserted-by":"crossref","unstructured":"Sun, J. et al. The Pseudomonas aeruginosa protease LasB directly activates IL-1\u03b2. EBioMedicine 60, 102984 (2020).","DOI":"10.1016\/j.ebiom.2020.102984"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.15.725401","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:40:20Z","timestamp":1779205220000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.15.725401"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":45,"URL":"https:\/\/doi.org\/10.64898\/2026.05.15.725401","relation":{"has-version":[{"id-type":"doi","id":"10.7554\/eLife.112023.1","asserted-by":"object"}]},"subject":[],"published":{"date-parts":[[2026,5,15]]},"subtype":"preprint"}}