Chen Carmen, Krzyżewska-Dudek Eva, Patpatia Sheetal, Dulipati Vinaya, Mapelli Sarah Natalia, Meral Aycan, Kotimaa Juha, Kiljunen Saija, Meri Seppo
Translational Immunology Research Program, Department of Bacteriology and Immunology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Department of Biomedical Sciences, Humanitas University, Milan, Italy.
Med Microbiol Immunol. 2025 Sep 2;214(1):40. doi: 10.1007/s00430-025-00852-0.
Infections caused by multidrug-resistant Acinetobacter baumannii are an emerging global health threat. Although phages have shown promising results in treating bacterial infections, the mechanisms of the combined effect of phages and innate immunity on clearing A. baumannii remain unclear. Here, we report a synergistic effect of the complement system and phages on clearing multidrug-resistant A. baumannii. We show that A. baumannii rapidly adapts and becomes resistant to phage or serum complement by modifying the expression of capsule and lipooligosaccharides, which can be regulated through reversible transposon mutagenesis in the K locus. Compared to the encapsulated phenotype, the non-encapsulated, phage-resistant A. baumannii showed a higher level of membrane attack complex deposition and were susceptible to killing by complement. In contrast, the encapsulated phenotype escaped the complement system by shedding the membrane attack complex to the environment. Thus, while the complement system targets the non-encapsulated phenotype, the phage infects and eliminates the encapsulated subpopulation. These results suggest means of combatting antibiotic-resistant A. baumannii by a simultaneous treatment with phages and complement, a combination which can be supplemented further with antibacterial antibodies.
多重耐药鲍曼不动杆菌引起的感染是一种新出现的全球健康威胁。尽管噬菌体在治疗细菌感染方面已显示出有前景的结果，但噬菌体与固有免疫在清除鲍曼不动杆菌方面的联合作用机制仍不清楚。在此，我们报道补体系统和噬菌体在清除多重耐药鲍曼不动杆菌方面的协同作用。我们表明，鲍曼不动杆菌通过改变荚膜和脂寡糖的表达迅速适应并对噬菌体或血清补体产生抗性，这可通过K位点的可逆转座子诱变来调控。与有荚膜表型相比，无荚膜、抗噬菌体的鲍曼不动杆菌表现出更高水平的膜攻击复合物沉积，且易被补体杀伤。相反，有荚膜表型通过将膜攻击复合物释放到环境中而逃避补体系统。因此，补体系统靶向无荚膜表型，而噬菌体感染并清除有荚膜亚群。这些结果提示了通过同时用噬菌体和补体治疗来对抗耐抗生素鲍曼不动杆菌的方法，这种联合疗法还可进一步补充抗菌抗体。
