Faculty of Medicine and Life Sciences, FI-33014 University of Tampere, Tampere, Finland.
Faculty of Medicine and Life Sciences, FI-33014 University of Tampere, Tampere, Finland
Dis Model Mech. 2018 Jan 29;11(1):dmm031658. doi: 10.1242/dmm.031658.
Mycobacterium tuberculosis remains one of the most problematic infectious agents, owing to its highly developed mechanisms to evade host immune responses combined with the increasing emergence of antibiotic resistance. Host-directed therapies aiming to optimize immune responses to improve bacterial eradication or to limit excessive inflammation are a new strategy for the treatment of tuberculosis. In this study, we have established a zebrafish- natural host-pathogen model system to study induced protective immune responses in mycobacterial infection. We show that priming adult zebrafish with heat-killed (HKLm) at 1 day prior to infection leads to significantly decreased mycobacterial loads in the infected zebrafish. Using fish, we show that the protective immunity conferred by HKLm priming can be induced through innate immunity alone. At 24 h post-infection, HKLm priming leads to a significant increase in the expression levels of macrophage-expressed gene 1 (), tumor necrosis factor α () and nitric oxide synthase 2b (), whereas superoxide dismutase 2 () expression is downregulated, implying that HKLm priming increases the number of macrophages and boosts intracellular killing mechanisms. The protective effects of HKLm are abolished when the injected material is pretreated with nucleases or proteinase K. Importantly, HKLm priming significantly increases the frequency of clearance of infection by evoking sterilizing immunity (25 vs 3.7%, =0.0021). In this study, immune priming is successfully used to induce sterilizing immunity against mycobacterial infection. This model provides a promising new platform for elucidating the mechanisms underlying sterilizing immunity and to develop host-directed treatment or prevention strategies against tuberculosis.This article has an associated First Person interview with the first author of the paper.
结核分枝杆菌仍然是最具问题的感染病原体之一，这是由于其高度发达的逃避宿主免疫反应的机制，加上抗生素耐药性的不断出现。旨在优化免疫反应以提高细菌清除率或限制过度炎症的宿主定向治疗是治疗结核病的一种新策略。在这项研究中，我们建立了一种斑马鱼-天然宿主-病原体模型系统，以研究结核分枝杆菌感染中诱导的保护性免疫反应。我们表明，在感染前 1 天用热灭活的（HKLm）对成年斑马鱼进行预处理可导致感染斑马鱼中的分枝杆菌负荷显著降低。使用 鱼，我们表明 HKLm 预处理诱导的保护性免疫可以仅通过先天免疫来诱导。感染后 24 小时，HKLm 预处理导致巨噬细胞表达基因 1（）、肿瘤坏死因子α（）和一氧化氮合酶 2b（）的表达水平显著增加，而超氧化物歧化酶 2（）的表达下调，这意味着 HKLm 预处理增加了巨噬细胞的数量并增强了细胞内杀伤机制。当注射材料用核酸酶或蛋白酶 K 预处理时，HKLm 的保护作用被消除。重要的是，HKLm 预处理通过引发杀菌免疫显著增加了清除 感染的频率（25 比 3.7%，=0.0021）。在这项研究中，免疫预处理成功地用于诱导针对分枝杆菌感染的杀菌免疫。该模型为阐明杀菌免疫的机制以及开发针对结核病的宿主定向治疗或预防策略提供了一个有前途的新平台。本文有该论文第一作者的相关第一人称采访。
