Department of Pediatrics, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, United States of America.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
PLoS Pathog. 2020 Mar 13;16(3):e1008374. doi: 10.1371/journal.ppat.1008374. eCollection 2020 Mar.
Antimicrobial resistance is increasing in pathogenic bacteria. Yet, the effect of antibiotic exposure on resistant bacteria has been underexplored and may affect pathogenesis. Here we describe the discovery that propagation of the human pathogen Acinetobacter baumannii in an aminoglycoside antibiotic results in alterations to the bacterium that interact with lung innate immunity resulting in enhanced bacterial clearance. Co-inoculation of mice with A. baumannii grown in the presence and absence of the aminoglycoside, kanamycin, induces enhanced clearance of a non-kanamycin-propagated strain. This finding can be replicated when kanamycin-propagated A. baumannii is killed prior to co-inoculation of mice, indicating the enhanced bacterial clearance results from interactions with innate host defenses in the lung. Infection with kanamycin-propagated A. baumannii alters the kinetics of phagocyte recruitment to the lung and reduces pro- and anti-inflammatory cytokine and chemokine production in the lung and blood. This culminates in reduced histopathologic evidence of lung injury during infection despite enhanced bacterial clearance. Further, the antibacterial response induced by killed aminoglycoside-propagated A. baumannii enhances the clearance of multiple clinically relevant Gram-negative pathogens from the lungs of infected mice. Together, these findings exemplify cooperation between antibiotics and the host immune system that affords protection against multiple antibiotic-resistant bacterial pathogens. Further, these findings highlight the potential for the development of a broad-spectrum therapeutic that exploits a similar mechanism to that described here and acts as an innate immunity modulator.
抗微生物药物耐药性在致病菌中不断增加。然而，抗生素暴露对抗耐药菌的影响尚未得到充分探索，可能会影响发病机制。在这里，我们描述了这样一个发现：在氨基糖苷类抗生素中培养人类病原体鲍曼不动杆菌会导致细菌发生变化，这些变化与肺部固有免疫相互作用，从而增强细菌清除。将在有和没有氨基糖苷类药物，即卡那霉素存在的情况下生长的鲍曼不动杆菌共同接种到小鼠体内，会诱导非卡那霉素传播株的清除率增强。当在共同接种到小鼠之前杀死用卡那霉素传播的鲍曼不动杆菌时，可以复制这种发现，表明增强的细菌清除是由于与肺部固有宿主防御的相互作用所致。用卡那霉素传播的鲍曼不动杆菌感染会改变吞噬细胞向肺部的募集动力学，并减少肺部和血液中促炎和抗炎细胞因子和趋化因子的产生。这导致在感染期间尽管细菌清除增强，但肺部组织病理学损伤的证据减少。此外，用已杀死的氨基糖苷类传播的鲍曼不动杆菌诱导的抗菌反应增强了感染小鼠肺部中多种临床相关革兰氏阴性病原体的清除。总之，这些发现体现了抗生素与宿主免疫系统之间的合作，为对抗多种抗抗生素的细菌病原体提供了保护。此外，这些发现突出了开发一种广谱治疗药物的潜力，该药物利用类似于此处所述的机制并作为固有免疫调节剂发挥作用。
