Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Mol Med Rep. 2019 May;19(5):4057-4066. doi: 10.3892/mmr.2019.10071. Epub 2019 Mar 21.
Burn‑site infections, commonly due to Pseudomonas aeruginosa, have been associated with deranged intestinal integrity, allowing bacteria and their products to translocate from the gut to the circulatory system. The P. aeruginosa quorum sensing (QS) transcription factor MvfR (PqsR) controls the expression of numerous virulence factors, and the synthesis of several toxic products. However, the role of QS in intestinal integrity alterations, to the best of our knowledge, has not been previously investigated. Using a proven anti‑MvfR, anti‑virulence agent, the in vivo results of the present study revealed that inhibition of MvfR function significantly decreased Fluorescein Isothiocyanate‑Dextran (FITC‑Dextran) flow from the intestine to the systemic circulation, diminished bacterial translocation from the intestine to mesenteric lymph nodes (MLNs), and improved tight junction integrity in thermally injured and infected mice. In addition, the MvfR antagonist administration alleviates the intestinal inflammation, as demonstrated by reduced ileal TNF‑α and fecal lipocalin‑2 concentrations. In addition, it is associated with lower levels of circulating endotoxin and decreased P. aeruginosa dissemination from the burn wound to the ileum. Collectively, these results hold great promise that the inhibition of this QS system mitigates gut hyperpermeability by attenuating the derangement of morphological and immune aspects of the intestinal barrier, suggesting that MvfR function is crucial in the deterioration of intestinal integrity following P. aeruginosa burn‑site infection. Therefore, an anti‑virulence approach targeting MvfR, could potentially offer a novel therapeutic approach against multi‑drug resistant P. aeruginosa infections following thermal injuries. Since this approach is targeting virulence pathways that are non‑essential for growth or viability, our strategy is hypothesized to minimize the development of bacterial resistance, and preserve the beneficial enteric microbes, while improving intestinal integrity that is deranged as a result of burn and infection.
烧伤部位感染通常是由铜绿假单胞菌引起的，与肠道完整性紊乱有关，使细菌及其产物从肠道转移到循环系统。铜绿假单胞菌群体感应（QS）转录因子 MvfR（PqsR）控制着许多毒力因子的表达和几种有毒产物的合成。然而，QS 在肠道完整性改变中的作用，据我们所知，尚未被先前研究过。本研究使用已被证实的抗 MvfR、抗毒力剂，体内结果表明，抑制 MvfR 功能可显著减少荧光素异硫氰酸酯-葡聚糖（FITC-葡聚糖）从肠道流向全身循环，减少细菌从肠道向肠系膜淋巴结（MLN）的转移，并改善热损伤和感染小鼠的紧密连接完整性。此外，MvfR 拮抗剂的给药可减轻肠道炎症，表现为回肠 TNF-α和粪便脂联素-2 浓度降低。此外，它与循环内毒素水平降低和铜绿假单胞菌从烧伤创面向回肠的传播减少有关。综上所述，这些结果表明，抑制该 QS 系统可通过减轻肠道屏障形态和免疫方面的紊乱来减轻肠道通透性增加，表明 MvfR 功能对铜绿假单胞菌烧伤部位感染后肠道完整性的恶化至关重要。因此，针对 MvfR 的抗毒力方法可能为热损伤后多药耐药铜绿假单胞菌感染提供一种新的治疗方法。由于这种方法针对的是对生长或存活非必需的毒力途径，我们的策略假设可以最大限度地减少细菌耐药性的发展，并保留有益的肠道微生物，同时改善因烧伤和感染而紊乱的肠道完整性。
