Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Heidelberg, Germany.
Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.
Front Immunol. 2019 Feb 21;10:198. doi: 10.3389/fimmu.2019.00198. eCollection 2019.
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 via endosomal Toll-like receptors (TLRs) . However, the individual contribution and cooperation between TLRs as well as cell-type and strain specific differences in dependency on nucleic acid detection during infection have not been clarified in detail. Moreover, the role of particularly bacterial RNA for the defense of infection 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 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 strains display a considerable inter-strain variability with respect to their nucleic acid dependent recognition. Moreover, TLR13-dependent recognition of 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 . , we show that a loss of nucleic acid sensing blunts early recognition of , 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 infection both and .
是一种主要的人类病原体，可引起多种疾病，从常见的咽炎到危及生命的软组织感染和败血症。最近，微生物核酸，特别是细菌 RNA，已被确认为涉及通过内体 Toll 样受体 (TLR) 检测 的主要病原体相关分子模式 (PAMP) 之一。然而，TLR 之间的个体贡献和合作，以及在 感染 过程中依赖核酸检测的细胞类型和菌株特异性差异，尚未得到详细阐明。此外，特别是细菌 RNA 对 感染 防御的作用仍未得到很好的定义。在这项研究中，我们报告说，在所研究的所有参与细菌感染缓解的固有免疫细胞中，包括鼠巨噬细胞、树突状细胞和中性粒细胞，在较低的 MOI 下，通过内体 TLR 识别 菌株 ATCC12344 几乎完全依赖于核酸感应，而在较高的 MOI 下，TLR2 的检测则发挥额外的、但冗余的作用。我们进一步证明，不同的 菌株在依赖核酸的识别方面表现出相当大的菌株间变异性。此外，TLR13 依赖性识别 RNA 在骨髓来源的巨噬细胞 (BMDM) 中基本上是非冗余的，但在中性粒细胞和骨髓来源的髓样树突状细胞 (BMDC) 中对于诱导先天免疫反应的相关性较小。 ，我们表明，核酸感应的丧失会削弱对 的早期识别，导致细菌感染的局部控制减弱，随后在稍后的时间点出现明显的全身炎症。因此，我们的研究结果表明，内体 TLR 通过核酸感应在防御 和 感染方面都起着至关重要的作用。
