Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
Uniformed Services University School of Medicine, Bethesda, Maryland, USA.
Clin Transl Sci. 2024 Jul;17(7):e13876. doi: 10.1111/cts.13876.
Plerixafor is a CXCR4 antagonist approved in 2008 by the FDA for hematopoietic stem cell collection. Subsequently, plerixafor has shown promise as a potential pathogen-agnostic immunomodulator in a variety of preclinical animal models. Additionally, investigator-led studies demonstrated plerixafor prevents viral and bacterial infections in patients with WHIM syndrome, a rare immunodeficiency with aberrant CXCR4 signaling. Here, we investigated whether plerixafor could be repurposed to treat sepsis or severe wound infections, either alone or as an adjunct therapy. In a Pseudomonas aeruginosa lipopolysaccharide (LPS)-induced zebrafish sepsis model, plerixafor reduced sepsis mortality and morbidity assessed by tail edema. There was a U-shaped response curve with the greatest effect seen at 0.1 μM concentration. We used Acinetobacter baumannii infection in a neutropenic murine thigh infection model. Plerixafor did not show reduced bacterial growth at 24 h in the mouse thigh model, nor did it amplify the effects of a rifampin antibiotic therapy, in varying regimens. While plerixafor did not mitigate or treat bacterial wound infections in mice, it did reduce sepsis mortality in zebra fish. The observed mortality reduction in our LPS model of zebrafish was consistent with prior research demonstrating a mortality benefit in a murine model of sepsis. However, based on our results, plerixafor is unlikely to be successful as an adjunct therapy for wound infections. Further research is needed to better define the scope of plerixafor as a pathogen-agnostic therapy. Future directions may include the use of longer acting CXCR4 antagonists, biased CXCR4 signaling, and optimization of animal models.
plerixafor 是一种 CXCR4 拮抗剂，于 2008 年被 FDA 批准用于造血干细胞采集。随后，plerixafor 在多种临床前动物模型中表现出作为潜在的无病原体免疫调节剂的潜力。此外，研究人员主导的研究表明，plerixafor 可预防 WHIM 综合征（一种具有异常 CXCR4 信号的罕见免疫缺陷）患者的病毒和细菌感染。在这里，我们研究了 plerixafor 是否可以单独或作为辅助治疗用于治疗败血症或严重的伤口感染。在铜绿假单胞菌脂多糖（LPS）诱导的斑马鱼败血症模型中，plerixafor 通过尾部水肿降低了败血症的死亡率和发病率。在 0.1μM 浓度下观察到 U 形反应曲线，效果最大。我们在中性粒细胞减少的小鼠大腿感染模型中使用鲍曼不动杆菌感染。在小鼠大腿模型中，24 小时时，plerixafor 并未显示出减少细菌生长的作用，也没有增强不同方案中利福平抗生素治疗的作用。虽然 plerixafor 没有减轻或治疗小鼠的细菌性伤口感染，但它确实降低了斑马鱼的败血症死亡率。我们在 LPS 诱导的斑马鱼模型中观察到的死亡率降低与先前的研究结果一致，该研究表明在败血症的小鼠模型中死亡率降低。然而，根据我们的结果，plerixafor 不太可能作为伤口感染的辅助治疗成功。需要进一步研究以更好地定义 plerixafor 作为无病原体治疗的范围。未来的研究方向可能包括使用作用时间更长的 CXCR4 拮抗剂、偏倚的 CXCR4 信号传导以及优化动物模型。
