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

IF 4.6 2区 医学 Q2 IMMUNOLOGY
Frontiers in Cellular and Infection Microbiology Pub Date : 2024-10-11 eCollection Date: 2024-01-01 DOI:10.3389/fcimb.2024.1444178
Abbie Hinds, Philip Ward, Nathan Archer, James Leigh
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引用次数: 0

Abstract

Introduction: Streptococcus uberis is a member of the pyogenic cluster of Streptococcus commonly associated with intramammary infection and mastitis in dairy cattle. It is a poorly controlled globally endemic pathogen responsible for a significant cause of the disease worldwide. The ruminant mammary gland provides an atypical body niche in which immune cell surveillance occurs on both sides of the epithelial tissue. S. uberis does not cause disease in non-ruminant species and is an asymptomatic commensal in other body niches. S. uberis exploits the unusual niche of the mammary gland to initiate an innate response from bovine mammary macrophage (BMMO) present in the secretion (milk) in which it can resist 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. In contrast to other bacteria pathogenic to the bovine mammary gland, S. uberis does not elicit innate responses from epithelial tissues; initial recognition of infection is via macrophages within milk.

Methods: We dissected the role of the bacterial protein SUB1154 in the inflammasome pathway using ex vivo bovine mammary macrophages isolated from milk, recombinant protein expression, and a panel of inhibitors, agonists, and antagonists. We combine this with reverse-transcription quantitative real-time PCR to investigate the mechanisms underlying SUB1154-mediated priming of the immune response.

Results: Here, we show that SUB1154 is responsible for priming the NLRP3 inflammasome in macrophages found in the mammary gland. 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. Surprisingly, only by blocking internalisation, or the cytoplasmic TIR domain of TLR2 were we able to block SUB1154-mediated priming.

Discussion: Together, our data unifies several contrasting past studies and provides new mechanistic understanding of potential early interactions between pyogenic streptococci and the host.

来自内部的引物:尤伯杯链球菌对乳腺巨噬细胞炎性体的激活依赖于 TLR2 但独立于受体。
导言:尤伯杯链球菌(Streptococcus uberis)是化脓性链球菌群中的一种,通常与奶牛乳房内感染和乳腺炎有关。它是一种控制不力的全球流行性病原体,是全球乳腺炎的主要病因。反刍动物乳腺提供了一个非典型体位,上皮组织两侧都有免疫细胞监测。乌贝氏菌在非反刍动物中不会致病,在其他体位中也是无症状的共生菌。乌贝氏菌利用乳腺的特殊生态位,从分泌物(牛奶)中的牛乳腺巨噬细胞(BMMO)启动先天性反应,从而抵抗宿主的免疫反应。因此,出乎意料的是,宿主炎症反应是 S.uberis 发病机制的关键步骤,没有宿主炎症反应,S.uberis 的定植就会受到影响。与其他对牛乳腺致病的细菌不同,S. uberis 不会引起上皮组织的先天性反应;感染的最初识别是通过牛奶中的巨噬细胞:方法:我们利用从牛奶中分离的体外牛乳腺巨噬细胞、重组蛋白表达以及一系列抑制剂、激动剂和拮抗剂,剖析了细菌蛋白 SUB1154 在炎性体通路中的作用。我们将其与反转录定量实时 PCR 结合起来,研究 SUB1154 介导的免疫反应启动机制:结果:我们在这里发现,SUB1154 负责启动乳腺巨噬细胞中的 NLRP3 炎性体。在没有 SUB1154 的情况下,IL-1β 不会产生,而我们能够利用重组 SUB1154 恢复 sub1154 缺失的 S. uberis 突变体对 IL-1β 的反应。令人惊讶的是,只有通过阻断内化或 TLR2 的胞质 TIR 结构域,我们才能阻断 SUB1154 介导的引物反应:总之,我们的数据统一了过去几项截然不同的研究,为化脓性链球菌与宿主之间潜在的早期相互作用提供了新的机制认识。
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
CiteScore
7.90
自引率
7.00%
发文量
1817
审稿时长
14 weeks
期刊介绍: Frontiers in Cellular and Infection Microbiology is a leading specialty journal, publishing rigorously peer-reviewed research across all pathogenic microorganisms and their interaction with their hosts. Chief Editor Yousef Abu Kwaik, University of Louisville is supported by an outstanding Editorial Board of international experts. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide. Frontiers in Cellular and Infection Microbiology includes research on bacteria, fungi, parasites, viruses, endosymbionts, prions and all microbial pathogens as well as the microbiota and its effect on health and disease in various hosts. The research approaches include molecular microbiology, cellular microbiology, gene regulation, proteomics, signal transduction, pathogenic evolution, genomics, structural biology, and virulence factors as well as model hosts. Areas of research to counteract infectious agents by the host include the host innate and adaptive immune responses as well as metabolic restrictions to various pathogenic microorganisms, vaccine design and development against various pathogenic microorganisms, and the mechanisms of antibiotic resistance and its countermeasures.
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