Our objectives

The overall goal with INFECT is to advance our understanding of the pathophysiological mechanisms, prognosis, and diagnosis of the multifactorial highly lethal necrotizing soft tissue infections (NSTIs).

The research in INFECT is focused on six distinct, yet highly integrated objectives.
Our objectives
The specific objectives of INFECT are to:

Unravel specific mechanisms underlying diseases signatures though a bottom-up systems approach applied to clinically relevant experimental

The major tasks here involve a model-driven, forward genetics approach using advanced murine models specifically optimized for NSTI infections (WP1), as well as a human 3D artificial skin tissue model system (WP6). By computer-assisted designs, these experimental models can be immediately employed to test pre-existing working hypotheses, including (i) the importance of a choice of susceptibility alleles and their influence on superantigen-signaling pathways and consequently the level of inflammatory responses; and (ii) host susceptibility determining cytotoxininduced cell death pathways and secondary inflammatory responses. The experimental strategy consists of “perturbing” the system (mouse or tissue) following specific model predictions and subsequently measuring a range of cellular and molecular responses. This will provide a mechanistic backbone that will assist in interpreting the top-down, systems-wide analyses from patient samples (as per objective 2).

Apply a top-down systems biology approach to NSTI patient samples to pin-point key host and pathogen factors involved in the onset and development of infection

This objective is based on a prospective patient cohort of NSTIs patients including a centralized registry to document clinical data and treatment strategies, which will be linked to an associated biobank and isolate collection (WP2). Patient enrolment will be achieved by The Scandinavian consortium for NSTI (partners 2, 3, 4, 5 and 6). System-wide ‘omics’ analyses (genomics-, transcriptomics-, proteomics-, metabolomics-analyses) entail both pathogen and human samples (WP3). Through solid multivariate statistics and mathematical treatment, the results of these analyses will pin-point factors/pathways/biomarker sets that contribute to disease and will be integrated with clinical data in WP4. In vivo expression of factors and their inter-relations will be explored in patient tissue biopsies which allows for direct assessment at the site of infection (WP5).

Identify and quantify disease signatures and underlying networks that contribute to disease outcome

To gain insights into the pathopysiology of NSTI, we will need to integrate in a structured, systems manner the information from personalized ‘omics’ analyses and other data with that of the clinical conditions and environmental setting. To this end, the multiple and heterogeneous data sets from WP1-3, 5 and 6 will be aggregated in a dynamic, relational database (WP4). Multivariate statistics, machine learning and reverse engineering approaches will allow pinpointing and mapping key nodes (and possible of biomarker sets) from heterogeneous (meta-)data both from the tested pathogens and the murine and human hosts. These top-down analyses will be iteratively combined with bottom-up modelling of specific subnetworks/biomarker sets previously identified in both the pathogens and host as being important for the onset of NSTIs. This highly iterative and multidisciplinary workflow will provide insights that will be invaluable towards the personalized pathophysiology of NSTI.

Identify novel therapeutic strategies for NSTI

Improvement of therapies for NSTI is a major aim of INFECT driven by the fact that these infections are associated with significant risk for loss of lives and limbs, even in young previously healthy individuals. This is tackled in two ways: (i) two novel therapeutic strategies (intravenous immunoglobulin; IVIG and hyperbaric oxygen treatment; HBO) will be explored for clinical efficacy and mechanistic action using data from the clinical registry (WP2), studies in the murine model (WP1), assessment of biopsies pre and post-therapy (WP5), and dosages studies in skin tissue models (WP6); and (ii) through identification of novel targets revealed by the integrated systems biology approach in WP1-WP6.

Exploit identified disease traits for the innovation of optimized diagnostic tools

This objective aims to exploit the results obtained through the integrated systems biology approach in a multiplex diagnostic tool (WP7), which will be directed towards the clinically relevant pathogens and pathogenic disease traits identified (WP1-6). To achieve this, a diagnostic SME (partner 12) will employ two strategies one applying compact sequencing (pathogen detection) and compact profiling (disease traits) – both multiplex diagnostic technologies.

Translate the advanced knowledge generated in INFECT into evidence-based guidelines for classification and management

The advanced knowledge of NSTIs generated by the above studies will be used to create evidence based guidelines for classification and management. The patient organization together with the NSTI clinical consortium provides excellent means for efficient dissemination of such guidelines and other advances made in the project, eg improved diagnosis and advanced insight into the pathophysiology, to relevant end-users, including medical staff, patients and their relatives, SMEs and researchers.