Significance
In 2021, antimicrobial-resistant bacteria were responsible for 1.14 million deaths and associated with 4.71 million deaths globally. Patients who experience sepsis often face a higher risk of reinfections and hospital readmissions. To combat this crisis, bacteriophages—viruses that infect and kill bacteria—are regaining interest as a potential solution. Here, we show that mice infected with extraintestinal pathogenic Escherichia coli and treated with phage HP3 not only recover from the initial infection but also gain protection against a secondary challenge with the same bacterial strain. The protective effect is dependent on the bacteriolytic action of the phage. These findings shift phages from being solely therapeutic antimicrobials to dual-action immunotherapeutics capable of both clearing and preventing bacterial infections.
Abstract
Bacteriophages, or phages, are viruses that target and infect bacteria. Due to a worldwide rise in antimicrobial resistance (AMR), phages have been proposed as a promising alternative to antibiotics for the treatment of resistant bacterial infections. Up to this point in history, phage use in preclinical animal studies, clinical trials, and emergency-use compassionate care cases has centered around the original observation from 1915 showing phage as lytic agent, and thus a treatment that kills bacteria. Here, we describe an activity associated with phage therapy that extends beyond lytic activity that results in long-term protection against reinfection. This activity is potent, providing almost complete protection against a second lethal infection for animals treated with phage therapy. The activity also reduced infection burden an astounding billion-fold over the control. Reinfection protection requires phage lytic killing of its target bacterium but is independent of additional phage therapy. The effect is not driven by phage alone, lingering phage resistors, or a sublethal inoculum. In vitro phage-lysed bacteria provide partial protection, suggesting a combination of phage-induced lytic activity and immune stimulation by phage treatment is responsible for the effect. These observations imply certain phages may induce host adaptive responses following the lysis of the infecting bacteria. This work suggests phage therapy may contain a dual-action effect, an initial treatment efficacy followed by a long-term protection against reoccurring infection, a therapeutic-vaccination mechanism of action.
Source: Proceedings of the National Academy of Sciences of the United States of America, https://www.pnas.org/doi/abs/10.1073/pnas.2423286122?af=R
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