Casilag Fiordiligie, Matarazzo Laura, Franck Sebastian, Figeac Martin, Michelet Robin, Kloft Charlotte, Carnoy Christophe, Sirard Jean-Claude
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France.
Freie Universitaet Berlin, Institute of Pharmacy, Department of Clinical Pharmacy & Biochemistry, D-12169 Berlin, Germany.
ACS Infect Dis. 2021 Aug 13;7(8):2164-2175. doi: 10.1021/acsinfecdis.1c00176. Epub 2021 Jul 14.
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 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 reducing the dose or regimen of antibiotics.
需要采用替代治疗策略来对抗细菌感染，以减少抗生素的使用。本研究检验了以下假设：刺激天然免疫受体Toll样受体4可与抗生素联合使用，以改善侵袭性肺炎的治疗效果。在呼吸道感染小鼠模型中测试了生物合成的单磷酰脂质A（MPLA）（一种临床批准的Toll样受体4激活剂）的疗效。有趣的是，给予阿莫西林或MPLA可使肺部和脾脏中的细菌载量降低400至11000倍，但与模拟治疗相比，并未提高生存率。单独给予MPLA和阿莫西林的组合可进一步将细菌定植和侵袭减少10至18倍，并显著改善对致命疾病的保护作用。在感染情况下联合给予MPLA和阿莫西林与血清中阿莫西林、促炎细胞因子和趋化因子浓度的短暂升高以及肺组织中免疫基因的表达有关。值得注意的是，全身和肺部的免疫激活在阿莫西林消除后仍持续存在，提示了一种两步协同抗感染效应，即快速的抗生素介导的细菌改变以及通过黏膜和全身免疫产生的持久影响。我们的概念验证研究首次证明，增强Toll样受体4信号传导可与抗生素协同作用，以提高细菌性肺炎的治疗效果，从而降低抗生素的剂量或疗程。
