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Cyclic Di-GMP Stimulates Protective Innate Immunity in Bacterial Pneumonia

机译：循环双GMP刺激细菌性肺炎的保护性先天免疫力。

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Innate immunity is the primary mechanism by which extracellular bacterial pathogens are effectively cleared from the lung. We have previously shown that cyclic di-GMP (c-di-GMP [c-diguanylate]) is a novel small molecule immunomodulator and immunostimulatory agent that triggers protective host innate immune responses. Using a murine model of bacterial pneumonia, we show that local intranasal (i.n.) or systemic subcutaneous (s.c.) administration of c-di-GMP prior to intratracheal (i.t.) challenge with Klebsiella pneumoniae stimulates protective immunity against infection. Specifically, i.n. or s.c. administration of c-di-GMP 48 and 24 h prior to i.t. K. pneumoniae challenge resulted in significantly increased survival. Pretreatment with c-di-GMP resulted in a 5-fold reduction in bacterial CFU in the lung (P < 0.05) and an impressive >1,000-fold decrease in CFU in the blood (P < 0.01). c-di-GMP administration stimulated a robust innate response to bacterial challenge, characterized by enhanced accumulation of neutrophils and αβ T cells, as well as activated NK and αβ T lymphocytes, which was associated with earlier and more vigorous expression of chemokines and type I cytokines. Moreover, lung macrophages recovered from Klebsiella-infected mice pretreated with c-di-GMP expressed greater quantities of inducible nitric oxide synthase and nitric oxide ex vivo than did macrophages isolated from infected mice pretreated with the control, c-GMP. These findings demonstrate that c-di-GMP delivered in either a compartmentalized or systemic fashion stimulates protective innate immunity in the lung and protects mice against bacterial invasion. We propose that the cyclic dinucleotide c-di-GMP may be used clinically as an effective immunomodulator, immune enhancer, and vaccine adjuvant to protect against respiratory infection and pneumonia in humans and animals.
机译：先天免疫是从肺中有效清除细胞外细菌病原体的主要机制。先前我们已经表明，环二GMP（c-di-GMP [c-二鸟苷酸]）是一种新型的小分子免疫调节剂和免疫刺激剂，可触发保护性宿主先天性免疫应答。使用细菌性肺炎的鼠模型，我们显示在气管内对其进行肺炎克雷伯菌肺炎攻击之前，对c-di-GMP进行局部鼻内（in）或全身皮下（sc）施用c-di-GMP可刺激针对感染。具体来说，或s.c.在i.t.之前48和24小时给予c-di-GMP K。肺炎攻击可显着提高生存率。用c-di-GMP预处理可导致肺部细菌CFU降低5倍（ P <0.05），血液中CFU显着降低> 1,000倍（ P <0.01）。 c-di-GMP给药刺激了对细菌攻击的强烈先天反应，其特征是嗜中性粒细胞和αβT细胞以及活化的NK和αβT淋巴细胞的积累增强，这与趋化因子和I型的更早，更旺盛的表达有关细胞因子。此外，用c-di-GMP预处理的 Klebsiella 感染小鼠中回收的肺巨噬细胞离体表达的诱导型一氧化氮合酶和一氧化氮的量比用对照c预处理的感染小鼠中分离的巨噬细胞高。 -GMP。这些发现表明，以隔室或全身方式递送的c-di-GMP刺激了肺中的保护性先天免疫，并保护了小鼠免于细菌入侵。我们建议，环状二核苷酸c-di-GMP可在临床上用作有效的免疫调节剂，免疫增强剂和疫苗佐剂，以预防人和动物的呼吸道感染和肺炎。

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