Knowledge mobilisation for policy development: implementing systems approaches through participatory dynamic simulation modelling.

BACKGROUND: Evidence-based decision-making is an important foundation for health policy and service planning decisions, yet there remain challenges in ensuring that the many forms of available evidence are considered when decisions are being made. Mobilising knowledge for policy and practice is an emergent process, and one that is highly relational, often messy and profoundly context dependent. Systems approaches, such as dynamic simulation modelling can be used to examine both complex health issues and the context in which they are embedded, and to develop decision support tools. OBJECTIVE: This paper reports on the novel use of participatory simulation modelling as a knowledge mobilisation tool in Australian real-world policy settings. We describe how this approach combined systems science methodology and some of the core elements of knowledge mobilisation best practice. We describe the strategies adopted in three case studies to address both technical and socio-political issues, and compile the experiential lessons derived. Finally, we consider the implications of these knowledge mobilisation case studies and provide evidence for the feasibility of this approach in policy development settings. CONCLUSION: Participatory dynamic simulation modelling builds on contemporary knowledge mobilisation approaches for health stakeholders to collaborate and explore policy and health service scenarios for priority public health topics. The participatory methods place the decision-maker at the centre of the process and embed deliberative methods and co-production of knowledge. The simulation models function as health policy and programme dynamic decision support tools that integrate diverse forms of evidence, including research evidence, expert knowledge and localised contextual information. Further research is underway to determine the impact of these methods on health service decision-making.

Pseudomonas signal molecule 3-oxo-C12-homoserine lactone interferes with binding of rosiglitazone to human PPARgamma.

Peroxisome proliferator activated receptor (PPARgamma) has been suggested as a target for anti-inflammatory therapy in chronic lung disease, including infection with Pseudomonas aeruginosa. However, the P. aeruginosa signal molecule N-(3-oxo-dodecanoyl)-l-homoserine lactone (3-oxo-C12-HSL) has been reported to inhibit function of PPARs in mammalian cells. This suggests that binding of 3-oxo-C12-HSL to PPARs could increase inflammation during P. aeruginosa infection, particularly if it could compete for binding with other PPAR ligands. We investigated the ability of 3-oxo-C12-HSL to bind to a PPARgamma ligand binding domain (LBD) construct, and to compete for binding with the highly active synthetic PPARgamma agonist rosiglitazone. We demonstrate that 3-oxo-C12-HSL binds effectively to the PPARgamma ligand binding domain, and that concentrations of 3-oxo-C12-HSL as low as 1 nM can effectively interfere with the binding of rosiglitazone to the PPARgamma ligand binding domain. Because 3-oxo-C12 HSL has been demonstrated in lungs during P. aeruginosa infection, blockade of PPARgamma-dependent signaling by 3-oxo-C12-HSL produced by the infecting P. aeruginosa could exacerbate infection-associated inflammation, and potentially impair the action of PPAR-activating therapy. Thus the proposed use of PPARgamma agonists as anti-inflammatory therapy in lung P. aeruginosa infection may depend on their ability to counteract the effects of 3-oxo-C12-HSL.

Pseudomonas aeruginosa quorum-sensing signal molecules interfere with dendritic cell-induced T-cell proliferation.

Pseudomonas aeruginosa releases a wide array of toxins and tissue-degrading enzymes. Production of these malicious virulence factors is controlled by interbacterial communication in a process known as quorum sensing. An increasing body of evidence reveals that the bacterial signal molecule N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) exhibits both quorum-sensing signalling and immune-modulating properties. Recently, yet another quorum-sensing signal molecule, the Pseudomonas quinolone signal (PQS), has been shown to affect cytokine release by mitogen-stimulated human T cells. In the present article we demonstrate that both OdDHL and PQS decrease the production of interleukin-12 (IL-12) by Escherichia coli lipopolysaccharide-stimulated bone marrow-derived dendritic cells (BM-DCs) without altering their IL-10 release. Moreover, BM-DCs exposed to PQS and OdDHL during antigen stimulation exhibit a decreased ability to induce T-cell proliferation in vitro. Collectively, this suggests that OdDHL and PQS change the maturation pattern of stimulated DCs away from a proinflammatory T-helper type I directing response, thereby decreasing the antibacterial activity of the adaptive immune defence. OdDHL and PQS thus seem to possess dual activities in the infection process: as inducers of virulence factors as well as immune-modulators facilitating the infective properties of this pathogen.

The immunomodulatory Pseudomonas aeruginosa signalling molecule N-(3-oxododecanoyl)-L-homoserine lactone enters mammalian cells in an unregulated fashion.

The Pseudomonas aeruginosa quorum-sensing signal molecule N-3-oxododecanoyl)-L-homoserine lactone (OdDHL) has been reported to affect the function of a wide range of mammalian cell types, including cells of the immune system. In T cells, it has been reported to inhibit the production of most cytokines, and it has been reported to inhibit the function of antigen-presenting cells. The intracellular target of OdDHL in these cells remains to be identified, although the lipophilic nature of the molecule suggested that the target could be membrane associated. We explored the association of radiolabelled OdDHL with the membrane and cytoplasm of Jurkat T-cell lines and of primary murine T cells and dendritic cells. We found that not only did 3H-OdDHL enter the cytoplasm of Jurkat cells without disproportionate association with the cell membrane, it also reached maximum levels in the cytoplasm very quickly, and that the intracellular concentration was proportional to the extracellular concentration. Similar results were obtained when 3H-OdDHL was incubated with primary murine T cells or cultured dendritic cells. In addition, we show that the cellular distribution of OdDHL does not significantly alter after stimulation of Jurkat cells or primary murine CD4 T cells with immobilized anti-CD3, with little activity being associated with nuclear fractions. Together, these data strongly suggest that OdDHL enters mammalian cells by passive mechanisms, and that it does not preferentially associate with the membrane or nucleus upon T-cell receptor ligation.