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INFECT Report Summary

Project ID: 305340
Funded under: FP7-HEALTH
Country: Sweden

Periodic Report Summary 4 - INFECT (Improving Outcome of Necrotizing Fasciitis: Elucidation of Complex Host and Pathogen Signatures that Dictate Severity of Tissue Infection)

Project Context and Objectives:
The overall goal of INFECT is to advance our understanding of the pathophysiological mechanisms, prognosis, and diagnosis of the multifactorial highly lethal necrotizing soft tissue infections (NSTIs). NSTI’s are rapidly spreading infections that may cause extensive soft tissue or limb loss, multiorgan failure and are associated with a considerable fatality rate. It is undisputed that rapid diagnosis and prompt intervention is directly related to survival. The initial presentation may be limited to unspecific symptoms such as tenderness, swelling, erythema and pain. Thus, diagnosis and management are difficult due to heterogeneity in clinical presentation, in co-morbidities and in microbiological aetiology. There is an urgent need for novel diagnostic and therapeutic strategies in order to improve outcome of NSTIs. To achieve this, a comprehensive and integrated knowledge of diagnostic features, causative microbial agent, treatment strategies, and pathogenic mechanisms (host and bacterial disease traits and their underlying interaction network) is required. INFECT is designed to obtain such insights through an integrated systems biology approach in patients and different clinically relevant experimental models.

Specific objectives of INFECT are to:
1. Unravel specific mechanisms underlying diseases responses through a bottom-up systems approach applied to clinically relevant experimental models
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
3. Identify and quantify disease signatures and underlying networks that contribute to disease outcome
4. Exploit identified disease traits for the innovation of optimized diagnostic tools
5. Translate the advanced knowledge generated into evidence-based guidelines for classification and management, and novel therapeutic strategies

We have gathered a team of multidisciplinary researchers, clinicians, SMEs and a patient organization, each with a unique expertise, technical platform and/or model systems that together provide the means to successfully conduct the multifaceted research proposed and efficiently disseminate/exploit the knowledge obtained.

The project builds on eight distinct, yet highly integrated, scientific work packages (WP), that are illustrated in the figure 1. The project is based on a material collected from NSTI patients (WP2) as well as experimental model systems (WP1 & 6). The work flow include a comprehensive set of analyses (WP3 and WP5) followed by integration of results in advanced computational platforms (WP4). The results will be translated into novel diagnostic tests (WP7) and improved patient management (WP2 & 8). Through a successful interaction between all partners and between WPs, major achievements have been made in INFECT as illustrated in Figure 2. Also shown is the impact of the progress made, which reflects the value of a systems medicine approach in infectious diseases.

Project Results:
One key experimental model is a mouse model of NSTI established in WP1. Infection with Streptococcus pyogenes NSTI isolates revealed a variation in severity of infection in genetically diverse mice. Further analyses identified a specific host response network, e.g. the IL1β network, that contributes to outcome of NSTI. Also host genetics is explored in specific humanized mice models, as well as different bacterial strains and species.
A central part of the project is enrolment of NSTI patients, which is achieved in WP2. As of now, >380 patients have been enrolled and samples collected for analyses in other WPs. The data shows that the NSTI cohort consists of NSTI patients infected with different bacterial species, predominantly β-hemolytic streptococcus in the monomicrobial cases. About half of patients have underlying conditions that may have increased their risk of infection. Different patterns of co-morbidities are seen in patient with varying bacterial infections.
WP3 aims to analyse patient samples and clinical isolates. The analyses have provided insight into pathogenic properties, and omics data have been generated and used to populate the computational database (WP4). The overall goal of WP4 is to identify major molecular interaction networks between human host and infectious bacteria. Analyses of omics data in WP3 and WP4 reveal distinct clusters of patients in part linked to microbial aetiology. Host and bacterial factors crucial for tissue pathology could be identified and serology screening approach showed that a lack of protective anti-streptococcal antibodies against streptococcal exotoxins represents a significant risk factor for the development of a NSTI.
WP5 focuses on analyses of host-microbe interactions at the infected tissue site using NSTI patient tissue biopsies. Analyses thus far indicate important differences between patients infected with different pathogens; thus, indicating pathogen-specific mechanisms. Also host factors associated with severity of tissue damage have been identified. A key finding was the identification of biofilm formation in streptococcal NSTI, which has important implications for antibiotic efficacy.
In WP6, organotypic skin is used to model skin infection with clinical bacterial strains isolated in INFECT. The main achievement includes the identification of bacterial disease traits which includes the findings of different bacterial growth states, e.g. biofilm, by group A streptococci and increased streptolysin activity in group G streptococci. This is of clinical relevance as it identifies novel virulence mechanisms and targets for diagnosis and intervention.

WP7 focuses on the exploiting of obtained results (clinically relevant pathogens and pathogenic disease traits) in the design of a diagnostics approach by applying compact sequencing (pathogen detection - DNA) and compact profiling (disease traits – antigens) – both multiplex diagnostic technologies. Improvements for the test prototypes have been done and the new improved tool is ready for clinical validation.

The work package WP8 focuses on dissemination and exploitation of the INFECT study as well as on dissemination of knowledge generated in INFECT. Numerous dissemination activities have been undertaken since the beginning of the project and include actions directed towards the health care, the scientific community, policy makers and the society at large. An external open access website ( is continuously updated.
WP9 focuses on providing an efficient project management for INFECT and its 14 partners. Main activities have been to ensure efficient communication between the participants in the project, data sharing and integration, and to ensure full compliance with all legal and EC requirements.

Potential Impact:
All partners’ activity within INFECT is well-integrated and interdependent, where one crucial component being the access to patient samples linked to clinical data, eg. a NSTI patient cohort and associated biobank (WP2). Accordingly, a primary objective and aim of The Scandinavian study group of NSTIs (partners 2-6) is to establish a prospective study of NSTI patients at the major referral centers in Denmark, Sweden and Norway in order to obtain clinical data together with “state of the art” collected blood and tissue samples. By means of extensive laboratory analysis (WP3, WP5), these patient samples will be linked to detailed clinical information collected in the clinical databases. Then, in combination with different experimental model systems (WP1 and WP6), and the centralized data management platform for data sharing and modelling (WP4), this will ultimately assist in identification of biomarker sets for development of novel diagnostics (WP7). Thus, the results from this systems medicine approach, utilizing the power of computational and mathematical modelling to integrate a variety of biological/medical data based on clinically defined problems relevant at different levels of disease, are expected to provide understanding of the pathophysiological mechanisms, prognosis, diagnosis and treatment of NSTIs. This will be of benefit for the patients as well as the society at large.

Expected outcome/impact of INFECT:

Patient benefits
• Evidence based guidelines for classification and management.
• Improved diagnostics.

Advances in the NSTI field
• Novel insights into the pathophysiology.
• The value of systems medicine in solving complex human infectious diseases.

Societal benefits
• Increased awareness of NSTIs.
• Reduction on health care costs.
• Design/optimization of future clinical trials.
• Fostering the competitiveness of SMEs and European innovation.
• Training of researchers and medical staff.

In conclusion, the INFECT consortium has established and proved the operational efficacy of an outstanding and unique system for collection of NSTI patients, advanced experimental model systems, and state-of-the-art analyses of samples. The information gathered will significantly contribute to further understanding of complex human and pathogen interaction and future prognostic/diagnostic markers may be demonstrated and current treatment procedures changed, thereby improving survival and subsequent quality of life for those patients who become victims of severe life threatening NSTI. Already we see the power of the multi-discplinary design of INFECT, supporting feasibility to achieve the expected outcomes.

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