巨噬細(xì)胞引起的噬菌體密度降低限制了體內(nèi)肺部噬菌體治療的效果

中文摘要：

抗微生物抵抗力的上升導(dǎo)致對(duì)評(píng)估噬菌體療法的新興趣。在小鼠模型中，針對(duì)銅綠假單胞菌引起的急性肺炎的高效治療依賴于噬菌體與中性粒細(xì)胞的協(xié)同抗菌活性。在這里，我們展示了荷蘭Liposoma巨噬細(xì)胞清除劑ClodronateLiposomes清除肺泡巨噬細(xì)胞（AM）縮短成年雄性小鼠的生存時(shí)間，但并未提高肺中銅綠假單胞菌的負(fù)荷。令人意外的是，在接受噬菌體治療后，AM清除的小鼠的肺中銅綠假單胞菌水平顯著低于免疫能力正常的小鼠。為了探討治療小鼠中AM缺失益處的潛在機(jī)制，我們開(kāi)發(fā)了一個(gè)關(guān)于噬菌體、細(xì)菌和先天免疫系統(tǒng)動(dòng)態(tài)的數(shù)學(xué)模型。根據(jù)數(shù)據(jù)擬合的模型的模擬結(jié)果表明，AM減少了肺中的噬菌體密度。我們實(shí)驗(yàn)確認(rèn)，在免疫能力正常的小鼠中，噬菌體在體內(nèi)衰減的速度比AM缺失的動(dòng)物快，且AM能夠吞噬治療性噬菌體。這些發(fā)現(xiàn)表明噬菌體、細(xì)菌與免疫系統(tǒng)之間的反饋?zhàn)饔迷谂R床環(huán)境中影響噬菌體療法的結(jié)果。

英文摘要：

The rise of antimicrobial resistance leads to renewed interest in evaluating phage therapy. In murine models highly effective treatment of acute pneumonia caused by Pseudomonas aeruginosa relies on the synergistic antibacterial activity of bacteriophages with neutrophils. Here, we show that depletion of alveolar macrophages (AM) shortens the survival of adult male mice without boosting the P. aeruginosa load in the lungs. Unexpectedly, upon bacteriophage treatment, pulmonary levels of P. aeruginosa are significantly lower in AM-depleted than in immunocompetent mice. To explore potential mechanisms underlying the benefit of AM-depletion in treated mice, we develop a mathematical model of bacteriophage, bacteria, and innate immune system dynamics. Simulations from the model fitted to data suggest that AM reduce bacteriophage density in the lungs. We experimentally confirm that the in vivo decay of bacteriophage is faster in immunocompetent compared to AM-depleted animals and that AM phagocytize therapeutic bacteriophage. These findings demonstrate the involvement of feedback between bacteriophage, bacteria, and the immune system in shaping the outcomes of phage therapy in clinical settings.

論文信息：

論文題目：Macrophage-induced reduction of bacteriophage density limits the efficacy of in vivo pulmonary phage therapy

期刊名稱：Nature Communications

時(shí)間期卷：16, Article number: 5725 (2025)

在線時(shí)間：2025年7月1日

DOI：doi.org/10.1038/s41467-025-61268-1

產(chǎn)品信息：

貨號(hào)：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes

辦事處：Target Technology(靶點(diǎn)科技)

Clodronate Liposomes氯膦酸鹽脂質(zhì)體清除肺泡巨噬細(xì)胞（AM），在細(xì)菌感染的炎性模型中單核巨噬細(xì)胞功能研究，荷蘭Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見(jiàn)刊于Nature Communications：巨噬細(xì)胞引起的噬菌體密度降低限制了體內(nèi)肺部噬菌體治療的效果

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體的材料和方法：

Macrophage depletion

AM depletion was obtained by the intra-tracheal administration a single dose of 400?µg of clodronate liposomes or empty liposomes (LIPOSOMA, city), four days prior infection. For the intra-tracheal administration, the mice were anesthetized by intraperitoneal injection of a mixture of two vol of ketamine (10?mg/mL) and one vol of xylazine (1?mg/mL) in a solution of NaCl 0.9%. The dose administrated to each mouse was adjusted to 0.01?mg of the ketamine-xylazine mixture per 1?g of body mass.　　

材料和方法文獻(xiàn)截圖：