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ORIGINAL RESEARCH article

Front. Cell. Infect. Microbiol.
Sec. Microbes and Innate Immunity
Volume 14 - 2024 | doi: 10.3389/fcimb.2024.1444178

Priming from within: TLR2 dependent but receptor independent activation of the mammary macrophage inflammasome by Streptococcus uberis Authors

Provisionally accepted
Abbie Hinds Abbie Hinds 1,2Philip Ward Philip Ward 3Nathan Archer Nathan Archer 1*James Leigh James Leigh 1
  • 1 School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, England, United Kingdom
  • 2 Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
  • 3 Division of Structural Biology, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, Medical Sciences Division, University of Oxford, Oxford, England, United Kingdom

The final, formatted version of the article will be published soon.

    Streptococcus uberis is a pyogenic Streptococcus commonly associated with intramammary infection and mastitis in dairy cattle. It is a poorly controlled, endemic pathogen responsible for a significant proportion of cases worldwide. S. uberis does not cause disease in non-ruminant species and is an asymptomatic commensal in most body niches. However, the ruminant mammary gland is an atypical body niche in which immune cell surveillance occurs on both sides of the epithelial tissue. S. uberis does not elicit responses from mammary gland epithelial tissues, but instead exploits the unusual body niche by initiating an innate response from bovine mammary macrophage (BMMO) present in the secretion (milk) in which it is resistant to the host immune responses. As a result – and unexpectedly - the host inflammatory response is a key step in the pathogenesis of S. uberis, without which colonisation is impaired. Prior work demonstrated that a sortase-anchored serine protease, SUB1154, elicits this host immune response via the NLRP3 inflammasome. Here, we isolate ex-vivo BMMOs and use them to show that SUB1154 is responsible for priming the NLRP3 inflammasome in host macrophages. Without SUB1154, IL-1β is not produced, and we were able to restore IL-1β responses to a sub1154 deletion S.uberis mutant using recombinant SUB1154. We dissect the role of SUB1154 in the inflammasome pathway using ex-vivo bovine mammary macrophage and a panel of inhibitors, agonists, and antagonists. Surprisingly, only by blocking internalisation, or the cytoplasmic TIR domain of TLR2 were we able to block SUB1154-mediated priming. Together, our data unifies several contrasting past studies and provides new mechanistic understanding of potential early interactions between pyogenic streptococci and the host.

    Keywords: Streptococcus, Mastitis, Inflammasome, TLR2, NLRP3

    Received: 05 Jun 2024; Accepted: 12 Sep 2024.

    Copyright: © 2024 Hinds, Ward, Archer and Leigh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Nathan Archer, School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, LE12 5RD, England, United Kingdom

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.