Alternative treatment strategies against bacterial infections are required to decrease the use of antibiotics. This study tested the hypothesis that stimulation of the innate immune receptor Toll-like receptor 4 can be combined with antibiotics to improve the treatment of invasive pneumonia. The efficacy of the biosynthetic monophosphoryl lipid A (MPLA), a clinically approved Toll-like receptor 4 activator, was tested in a mouse model of Streptococcus pneumoniae respiratory infection. Interestingly, administration of amoxicillin or MPLA decreased 400- to 11 000-fold the bacterial load in the lungs and spleen but did not enhance survival compared to mock treatment. The single administration of a combination of MPLA and amoxicillin further reduced 10- to 18-fold the bacterial colonization and invasion and significantly improved protection against lethal disease. The combined administration of MPLA and amoxicillin in a context of infection was associated with transient increase of the serum concentrations of amoxicillin and pro-inflammatory cytokines and chemokines as well as the expression of immune genes in lung tissue. Remarkably, the systemic and lung immune activation extended beyond amoxicillin elimination, suggesting a two-step and cooperative anti-infective effect, i.e., rapid antibiotic-mediated alteration of bacteria and a long-lasting impact through mucosal and systemic immunity. Our proof-of-concept study demonstrated for the first time that boosting Toll-like receptor 4 signaling can synergize with antibiotics in order to increase the efficacy of therapy of bacterial pneumonia, thereby in fine reducing the dose or regimen of antibiotics.

中文翻译：

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生物合成单磷酰脂质 A 可提高肺炎球菌肺炎抗生素治疗的疗效

需要针对细菌感染的替代治疗策略来减少抗生素的使用。这项研究检验了以下假设：刺激先天免疫受体 Toll 样受体 4 可以与抗生素联合使用，以改善侵袭性肺炎的治疗。在肺炎链球菌小鼠模型中测试了生物合成单磷酰脂质 A (MPLA)（一种临床批准的 Toll 样受体 4 激活剂）的功效呼吸道感染。有趣的是，与模拟治疗相比，服用阿莫西林或 MPLA 可使肺和脾中的细菌负荷降低 400 至 11 000 倍，但并未提高存活率。MPLA 和阿莫西林组合的单次给药进一步减少了 10 到 18 倍的细菌定植和入侵，并显着改善了对致命疾病的保护。MPLA 和阿莫西林在感染情况下的联合给药与阿莫西林和促炎细胞因子和趋化因子的血清浓度的短暂增加以及肺组织中免疫基因的表达有关。值得注意的是，全身和肺免疫激活超出了阿莫西林的消除，表明具有两步协同抗感染作用，即，抗生素介导的细菌快速改变以及通过粘膜和全身免疫产生持久影响。我们的概念验证研究首次证明，增强 Toll 样受体 4 信号可以与抗生素协同作用，从而提高细菌性肺炎的治疗效果，从而在精细减少抗生素的剂量或方案。