Targeting bacterial quorum sensing shows promise in improving intestinal barrier function following burn‑site infection

Abstract

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.

Targeting the gut to prevent sepsis from a cutaneous burn

“…We and other groups show that in the context of a 30% total body surface area (TBSA) burn alone, intestinal permeability increases over time and peaks around 4-6 hours after the burn injury and then gradually returns to the homeostatic levels (11,29). However, the burned mice that receive an additional eschar infection show a dramatically increased gut permeability compared with burn alone, which continues over time and leads to a greater systemic inflammation and eventual death (11). To determine whether IAP supplementation can also benefit the host after burn injury alone without wound infection, we performed a 30% TBSA dorsal burn injury murine model and supplemented the treatment group with 2000 units of IAP 2 hours after the insult.…”

“…Thermal injury itself without wound infection negatively affects gut barrier function (2). We and other groups show that in the context of a 30% total body surface area (TBSA) burn alone, intestinal permeability increases over time and peaks around 4-6 hours after the burn injury and then gradually returns to the homeostatic levels (11,29). However, the burned mice that receive an additional eschar infection show a dramatically increased gut permeability compared with burn alone, which continues over time and leads to a greater systemic inflammation and eventual death (11).…”

“…We have previously shown that in the context of 30% TBSA burn alone, intestinal permeability increases over time and peaks around 4-6 hours after the burn injury and then gradually returns to the homeostatic levels (11). However, the burn-injured mice that received an additional eschar infection showed a dramatically increased gut permeability compared with burn alone, which continued over time (11). Considering the difference in the timing of the gut permeability peak after burn alone versus burn wound infection, the burnt mice were sacrificed at 6 hours after the burn insult, whereas the mice in the burn site infection group were sacrificed at 18 hours after the burn wound infection insult.…”

“…The resultant systemic inflammatory response further injures the gut barrier, establishing a "vicious cycle" of inflammation (2)(3)(4)(5)(6)(7). Furthermore, burn wound infection is a frequent complication of burn injury, compounding the initial insult and further affecting the gut barrier (2,(8)(9)(10)(11).…”

Rosmarinus officinalis L. (Rosemary) Extracts Containing Carnosic Acid and Carnosol are Potent Quorum Sensing Inhibitors of Staphylococcus aureus Virulence

“…The virulence factors produced by pathogenic organisms such as proteases, toxins, and biofilms, are largely responsible for the damage caused to the host tissue. As such, inhibiting these virulence factors, also known as anti-virulence technology, has emerged as an attractive therapeutic alternative to antibiotics [17,19,40]. It is supposed that by specifically targeting the mechanisms of bacterial virulence, and not viability, the pathogenicity of the bacteria can be controlled without increasing the chance of developing a resistant phenotype.…”