Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes.

IF 9 2区医学 Q1 CELL BIOLOGY

Journal of Biomedical Science Pub Date : 2024-02-27 DOI:10.1186/s12929-024-01014-9

Lea A Tölken, Antje D Paulikat, Lana H Jachmann, Alexander Reder, Manuela Gesell Salazar, Laura M Palma Medina, Stephan Michalik, Uwe Völker, Mattias Svensson, Anna Norrby-Teglund, Katharina J Hoff, Michael Lammers, Nikolai Siemens

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引用次数: 0

Abstract

Background: Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild superficial infections of the throat and skin to severe invasive infections, such as necrotizing soft tissue infections (NSTIs). Tissue passage of GAS often results in mutations within the genes encoding for control of virulence (Cov)R/S two component system leading to a hyper-virulent phenotype. Dendritic cells (DCs) are innate immune sentinels specialized in antigen uptake and subsequent T cell priming. This study aimed to analyze cytokine release by DCs and other cells of monocytic origin in response to wild-type and natural covR/S mutant infections.

Methods: Human primary monocyte-derived (mo)DCs were used. DC maturation and release of pro-inflammatory cytokines in response to infections with wild-type and covR/S mutants were assessed via flow cytometry. Global proteome changes were assessed via mass spectrometry. As a proof-of-principle, cytokine release by human primary monocytes and macrophages was determined.

Results: In vitro infections of moDCs and other monocytic cells with natural GAS covR/S mutants resulted in reduced secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, moDC maturation remained unaffected. Inhibition of caspase-8 restored secretion of both molecules. Knock-out of streptolysin O in GAS strain with unaffected CovR/S even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced NSTI GAS isolates, 28 harbored mutations resulting in dysfunctional CovR/S. However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence or absence of such mutations.

Conclusions: Our data demonstrate that strains, which harbor covR/S mutations, interfere with IL-18 and IL-8 responses in monocytic cells by utilizing the caspase-8 axis. Future experiments aim to identify the underlying mechanism and consequences for NSTI patients.

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人类单核细胞在感染高致病性化脓性链球菌后分泌的白细胞介素-18减少。

背景：化脓性链球菌（A 组链球菌，GAS）可引起多种疾病，从轻微的咽喉和皮肤浅表感染到严重的侵袭性感染，如坏死性软组织感染（NSTI）。组织通过 GAS 往往会导致编码控制毒力（Cov）R/S 双组分系统的基因发生突变，从而形成高毒力表型。树突状细胞（DC）是先天性免疫哨兵，专门从事抗原摄取和随后的 T 细胞引物。本研究旨在分析 DC 和其他单核细胞来源的细胞因子在野生型和天然 covR/S 突变型感染中的释放情况。方法：使用人类原代单核细胞衍生（mo）DC，通过流式细胞仪评估DC对野生型和covR/S突变体感染的成熟度和促炎细胞因子的释放。通过质谱法评估了全局蛋白质组的变化。作为原理验证，还测定了人类原代单核细胞和巨噬细胞的细胞因子释放量：结果：与野生型感染相比，moDCs 和其他单核细胞体外感染天然 GAS covR/S 突变体会导致 IL-8 和 IL-18 的分泌减少。相比之下，moDC 的成熟仍然不受影响。抑制 caspase-8 可恢复这两种分子的分泌。在CovR/S未受影响的GAS菌株中敲除链溶菌素O甚至进一步提高了moDCs的IL-18分泌。在 67 个完全测序的 NSTI GAS 分离物中，28 个存在导致 CovR/S 功能障碍的突变。然而，血浆中IL-8和IL-18水平的分析与是否存在此类突变无关：我们的数据表明，携带covR/S突变的菌株会利用caspase-8轴干扰单核细胞中的IL-18和IL-8反应。未来的实验旨在确定潜在的机制和对 NSTI 患者的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Biomedical Science 医学-医学：研究与实验

CiteScore

18.50

自引率

0.90%

发文量

审稿时长

1 months

期刊介绍： The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.