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Front. Immunol. | doi: 10.3389/fimmu.2019.00198

Crucial role of nucleic acid sensing via endosomal Toll-like receptors for the defense of Streptococcus pyogenes in vitro and in vivo

 Anna Hafner1, 2, Ulrike Kolbe2,  Isabel Freund2, Virginia Castiglia3,  Pavel Kovarik3, Tanja Poth2,  Franziska Herster4, Markus A. Weigand1,  Alexander N. Weber4,  Alexander H. Dalpke2 and  Tatjana Eigenbrod2*
  • 1Klinik für Anästhesiologie, Universitätsklinikum Heidelberg, Germany
  • 2Department für Infektiologie, Heidelberg University Hospital, Germany
  • 3Max F. Perutz Laboratories, University of Vienna, Austria
  • 4Department für Immunologie, Tübingen University Medical Center, Germany

Streptococcus pyogenes is a major human pathogen causing a variety of diseases ranging from common pharyngitis to life-threatening soft tissue infections and sepsis. Microbial nucleic acids, especially bacterial RNA, have recently been recognized as a major group of pathogen-associated molecular patterns (PAMPs) involved in the detection of Streptococcus pyogenes via endosomal Toll-like receptors (TLRs) in vitro. However, the individual contribution and cooperation between TLRs as well as cell-type and strain specific differences in dependency on nucleic acid detection during S. pyogenes infection in vitro have not been clarified in detail. Moreover, the role of particularly bacterial RNA for the defense of S. pyogenes infection in vivo remains poorly defined. In this study, we report that in all investigated innate immune cells involved in the resolution of bacterial infections, including murine macrophages, dendritic cells and neutrophils, recognition of S. pyogenes strain ATCC12344 is almost completely dependent on nucleic acid sensing via endosomal TLRs at lower MOIs, whereas at higher MOIs, detection via TLR2 plays an additional, yet redundant role. We further demonstrate that different S. pyogenes strains display a considerable inter-strain variability with respect to their nucleic acid dependent recognition. Moreover, TLR13-dependent recognition of S. pyogenes RNA is largely non-redundant in bone marrow-derived macrophages (BMDMs), but less relevant in neutrophils and bone marrow-derived myeloid dendritic cells (BMDCs) for the induction of an innate immune response in vitro. In vivo, we show that a loss of nucleic acid sensing blunts early recognition of S. pyogenes, leading to a reduced local containment of the bacterial infection with subsequent pronounced systemic inflammation at later time points. Thus, our results argue for a crucial role of nucleic acid sensing via endosomal TLRs in defense of S. pyogenes infection both in vitro and in vivo.

Keywords: Streptococcus pyogenes, bacterial RNA, Nucleic Acids, TLR13, UNC93B1, innate immunity, Skin Infection

Received: 20 Aug 2018; Accepted: 23 Jan 2019.

Edited by:

Amy Rasley, Lawrence Livermore National Laboratory, United States Department of Energy (DOE), United States

Reviewed by:

Arup Sarkar, Trident Academy of Creative Technology, India
Holger Heine, Forschungszentrum Borstel (LG), Germany  

Copyright: © 2019 Hafner, Kolbe, Freund, Castiglia, Kovarik, Poth, Herster, Weigand, Weber, Dalpke and Eigenbrod. 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) and the copyright owner(s) 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: Dr. Tatjana Eigenbrod, Heidelberg University Hospital, Department für Infektiologie, Heidelberg, 69120, Baden-Württemberg, Germany,