Haas, T. | bioRxiv Science

bioRxiv2021

The expression of virulence increases outer-membrane permeability and sensitivity to envelope stress in Salmonella Typhimurium

Environmental cues modulate the expression of virulence in bacterial pathogens. However, while cues that upregulate virulence are often intuitive and mechanistically well understood, this is less so for cues that downregulate virulence. In this study, we noticed that upregulation of the HilD virulence regulon in Salmonella Typhimurium (S.Tm) sensitized cells to membrane stress mediated by cholate, Tris/EDTA or heat. Further monitoring of membrane status and stress resistance of S.Tm cells in relation to virulence expression, revealed that co-expressed virulence factors embedded in the envelope (including the Type Three Secretion System 1 and the flagella) increased permeability, and stress sensitivity of the membrane. Importantly, pretreating the bacteria by sublethal stress inhibited virulence expression and restored stress resistance. As such, these results demonstrate a trade-off between virulence and stress resistance, which explains the downregulation of virulence expression in response to harsh environments in S.Tm.

microbiology↗

bioRxiv2020

Liquid foam therapy (LiFT) for homogenous distribution of exogenous pulmonary surfactant in ARDS

Lung surfactant dysfunction has a critical role in the pathophysiology of acute respiratory distress syndrome (ARDS). Yet, efforts to treat ARDS patients with liquid instillations of exogenous surfactant have so far failed. One of the ongoing challenges in surfactant therapy is obtaining a homogeneous distribution of surfactant within the lungs despite an inherent tendency to non-uniform spreading, owing amongst others to the influence of gravity. Here, we show that liquid foam therapy (LiFT), where surfactant is foamed prior to intratracheal administration, may improve notably surfactant distribution while maintaining safety and efficacy. We first show quantitatively that a foamed surrogate surfactant solution distributes more uniformly in ex vivo pig lungs compared to endotracheal instillations of the liquid solution, while maintaining pulmonary airway pressures within a safe range. Next, we demonstrate that a foamed commercial surfactant preparation (Infasurf) is effective in an established in vivo rat lung lavage model of ARDS. Our results suggest that LiFT may be more effective than liquid instillations for treating ARDS and serve as a proof-of-principle towards large animal and clinical trials.

pharmacology and toxicology↗