Canadian-German Collaboration on Infectious Disease Research Stage II Meeting Report
Braunschweig, Germany
March 22-23, 2007
Table of Contents
Executive Summary
Background
Meeting Objectives
Meeting Overview
- Welcome and Opening Remarks
- Overview of the Canadian Pandemic Preparedness Strategic Research Initiative and German Flu Network
- Development of Project Activities in Strategic Priority Areas
- Intellectual Property
- Mechanisms to Support the Research Projects and the Collaboration
Summaries of Research Programs in Strategic Priority Area
- Genetic and environmental determinants of immune response to inactivated influenza vaccination
- Large-scale mutagenesis screen to identify genetic determinants of host susceptibility to influenza
- Mucosal vaccination strategies against influenza in high risk populations
- Systems approach to new antimicrobial agents
- Functional genomics and multidrug resistance in Pseudomonas aeruginosa
Appendix 1: Members of the Organizing Committee
Appendix 2: List of Participants
Appendix 3: Meeting Agenda
Appendix 4: Detailed Research Proposals in Strategic Priority Areas
Appendix 5: Feedback on the Meeting from Participants
Executive Summary
The purpose of this report is to summarize the proceedings of the meeting of the Canadian-German Collaboration on Infectious Disease held in Braunschweig, Germany on March 22-23, 2007. The Collaboration consists of researchers and infectious disease experts from Canada and Germany who are committed to harnessing expertise and resources in both countries to establish innovative and collaborative research programs with the potential to have major impact on human and animal health.
The Collaboration was established at a meeting of infectious disease researchers and experts from both countries held in Montreal, Canada in November 2006. At the Montreal meeting, respiratory infectious diseases, particularly influenza, arose as an overall area for collaboration because there is scientific and public concern about a possible influenza pandemic that would have a major impact worldwide. Five strategic priority areas related to this theme were identified:
- Genetic determinants of vaccine/immunization response
- New strategies to vaccinate against respiratory pathogens
- Genetics of susceptibility to respiratory infections
- Microbial virulence and antibiotic resistance
- Microevolution of bacteria in cystic fibrotic lungs
The main goal of the meeting in Braunschweig was to formulate detailed research proposals in the five strategic priority areas and to move the projects to the point where researchers could begin the research phase of the program. Other objectives were to discuss funding opportunities and other mechanisms to support and nurture the Collaboration.
Participants discussed and reached agreement on detailed research projects within the strategic priority areas. This included the development of specific research objectives, a project description, and a detailed plan of action. Mechanisms to protect the intellectual property arising from the collaborative research were also discussed, and it was decided that an intellectual property agreement for the Collaboration will be developed. In addition, participants agreed that the Collaboration would be strengthened by the establishment of a more formalized network.
The projects that were discussed and developed at the meeting Braunschweig are innovative, ambitious and are truly collaborative in nature. The work that is planned requires the joint efforts, resources and expertise of researchers in both countries. Working together in this manner will create a synergism and add value to the project results. The results of the research and the products that are developed through the Collaboration promise to have a major impact on the prevention and treatment of acute and chronic respiratory diseases, including pandemic influenza, which is currently predicted to have major social and economic effects and cause numerous deaths worldwide.
The organizers and participants of the meeting were very pleased with the spirit of collegiality, enthusiasm and camaraderie among participants and the progress that was made.
Background
The Canadian-German Collaboration on Infectious Disease Research was established at a meeting of researchers and infectious disease experts from both countries held in Montreal in November 2006 under the auspices of the Agreement on Scientific and Technical Cooperation between Germany and Canada. The meeting was organized and/or sponsored by the Canadian Institutes of Health Research (CIHR), the Helmholtz Centre for Infection Research and the Federal Ministry of Education and Research (BMBF).
Participants at the Montreal meeting exchanged information about infectious diseases research in Germany and Canada and developed priorities in five strategic areas where a critical mass of expertise, facilities and resources exists in both countries and where there is a clear possibility of substantial scientific progress in a number of feasible collaborative projects with the potential for major impact on human and animal health. As the meeting progressed, respiratory infectious diseases, particularly influenza, arose as an overall strategic area for collaboration. The reasons for this are that both countries have the research capacity and strength to study respiratory diseases at several levels, and that there is scientific and public concern about a possible influenza pandemic that would affect both countries.
To keep the momentum of excitement and determination to succeed that was evident during the Montreal meeting going and to formulate research proposals in the priority areas, a second meeting of the Canadian-German Collaboration on Infectious Disease Research was held in Braunschweig, Germany on March 22-23, 2007. Participants included German and Canadian researchers and infectious disease experts in the priority areas identified at the first meeting, many of whom had attended the meeting in Montreal. This second meeting (stage II) was sponsored by the Helmholtz Centre for Infection Research, the CIHR and Foreign Affairs and International Trade Canada. See Appendix 1 for a list of organizing committee members and Appendix 2 for meeting participants.
Meeting Objectives
The purpose of the stage II meeting was to solidify the partnerships established in Montreal, to proceed with development of proposals, and to move the projects to the point where researchers could begin the research phase of the program. Primary objectives were:
- Specification and development of project activities for five identified research priority areas:
- Genetic determinants of vaccine/immunization response
- Genetics of susceptibility to respiratory infections
- New strategies to vaccinate against respiratory pathogens
- Microbial virulence and antibiotic resistance
- Microevolution of bacteria in cystic fibrotic lungs
- Discussion of funding opportunities.
- Discussion of overall strategies.
Meeting Overview
Dr. Bhagirath Singh, Director of the CIHR Institute of Infection and Immunity welcomed participants to the meeting, described the history of the Canadian-German Collaboration of Infectious Disease Research and outlined the objectives of the meeting. Dr. Emil Skamene, Co-chair of the meeting organizing committee told participants that the meeting afforded them the opportunity to develop important international collaborations including the formation of a clinical research network, training programs and linkages with industry. Dr. Rudi Balling Director of the Helmholtz Centre for Infection Research stated that the bi-national proposals that they develop at the meeting will increase competitiveness in securing national and international funding. He also said that he hoped that the open discussions that were evident at the meeting in Montreal would carry forward and develop further at the meeting in Braunschweig.
Overview of the Canadian Pandemic Preparedness Strategic Research Initiative and the German Flu Network
In keeping with the theme of the meeting, Dr. Singh gave an overview of the Pandemic Preparedness Strategic Research Initiative (PPSRI) that is being led by his Institute at CIHR, and related research funding opportunities that are available through the initiative. Grants have been awarded and additional RFAs have been launched or are planned in four identified research areas:
- Vaccines and immunization programs
- Biology of the influenza virus
- Prevention and treatment
- Ethics, legal and social research
Dr. Stefan Ludwig of the University of Muenster then summarized the activities of the German Flu Research Network and opportunities for research. The Network is composed of researchers from several academic institutions with expertise in veterinary medicine, molecular pathogenesis of influenza and clinical infectious disease. It has international linkages with the US, Canada and Switzerland. The overall goal of the network is to determine the molecular signatures of pathogenicity and species transmission of the influenza A virus. Questions that are being addressed are:
- When and why some viral strains cross the species barrier?
- Why are some viral strains highly pathogenic?
- What are the viral and cellular factors that determine pathogenicity?
Development of Project Activities in Strategic Priority Areas
Participants gathered in groups to develop detailed joint grant applications in five strategic priority areas:
- Genetic determinants of vaccine/immunization response
- New strategies to vaccinate against respiratory pathogens
- Genetics of susceptibility to respiratory infections
- Microbial virulence and antibiotic resistance
- Microevolution of bacteria in cystic fibrotic lungs
Each group discussed and reached agreement on detailed research projects within their strategic priority area. This included the development of specific research objectives, a project description, and a detailed plan of action with a description of research activities, timelines, a list of the specific contributions to be made by researchers in both countries, and areas for interaction with other groups within and outside the Collaboration. Team presentations were made in plenary, and the discussions were used to refine the projects. Summaries of the projects are found in this report following the Meeting Summary. Detailed descriptions of the research proposals are found in Appendix 4.
Towards the end of the first day, a presentation was made by Dr. Christian Stein from Ascenion GmbH, which specializes in intellectual property protection and management in the life sciences. Dr. Stein described the need for a Collaboration agreement that would oversee co-operation on all levels such as securing intellectual property and results/materials, establishing ownership of intellectual property, securing freedom to operate to enable commercial development of the results, and determining responsibility for commercial exploitation.
Dr. Stein's presentation was followed by a discussion about the best approach to handle the intellectual property that is expected to be generated by the activities of the members of the Collaboration. Participants stated that intellectual property agreements can be difficult when institutions and multiple countries are involved. Canadian participants stated that the National Centres of Excellence in Canada have developed strategies to deal with these difficulties and are sources of useful examples of intellectual property agreements. There was a consensus that agreements concerning intellectual property must be established before the research begins. Dr. Stein was asked to be the German intellectual property representative, and the group agreed that a suitable Canadian expert would be selected to work with Dr. Stein in order to develop an agreement.
Mechanisms to Support the Research Projects and the Collaboration
On the second day of the meeting, participants discussed and identified grant opportunities and other mechanisms to secure funding for the research projects that they had developed. Several organizations were named, and participants volunteered to approach these organizations.
Dr. Balling suggested that it might be a good idea to establish a network to frame, nurture and develop the Collaboration. He originally proposed the idea of network, which he called Fire and Ice (*/Fi/*ghting /*re*/spiratory infections-/*I*/nternational */C/*enter of /*E*/xcellence) at the meeting in Montreal. A network would have advantages in that it would provide a way for all researchers within the Collaboration to meet and interact, especially since many of the proposed projects have the potential for interaction between researchers from different priority areas. The network would also provide the structure and a mechanism to establish larger training programs. Participants at the meeting in Germany were enthusiastic about idea of the network and recommended that work to establish the network should begin as soon as possible. Potential mechanisms to fund and establish the network were discussed.
Summaries of Research Programs in Strategic Priority Areas
Genetic and environmental determinants of immune response to inactivated influenza vaccination
Coordinators: Mark Loeb and Stefan Meuer
Vaccination against influenza is considered the cornerstone for prevention. It is well accepted that vaccination during a pandemic, when the entire population will have no pre-existing immunity to the virus, will be the most important means of protection. However, little is known about the genetic determinants of a protective immune response following immunization with inactivated influenza vaccine. In addition, diminished responses to vaccination have been widely documented in the elderly, but the genetic and environmental causes for this observation are unknown.
The main goal of this research program is to identify the genetic and environmental factors that specify how the human immune system responds to influenza vaccination and to determine how these are affected by aging. Three groups of participants (children, adults, and adults over 65 years of age) in both Germany and Canada will be vaccinated with an inactivated influenza vaccine. Antibodies in the blood from the individuals that interact with components of the influenza virus will be measured before and after vaccination to determine the effectiveness of the vaccine in each individual. The expression of genes involved in the immune response will be measured following vaccination by gene expression profiling of immune cells to determine whether expression of specific genes is correlated with the development of protective antibodies against the influenza virus. The genotypes of the individuals will also be examined to determine if there is a correlation between specific genotypes and protective immune responses. The data from each age group will be compared to determine how the immune response to influenza vaccination changes with aging.
There is complementary expertise amongst the team members that is needed to carry out this research program. The gene expression profiling will be performed in Germany and the genotyping will be performed in Canada. Within the Collaboration, there is strong potential for synergy with the vaccine development group and with the group assessing genetic susceptibility to influenza in animal models. For example, genes identified by the latter group will be integrated into the genotyping studies.
Since ethnically different populations are likely to have conserved different components of immune response genes during evolution, it is essential to validate the genetic studies obtained in one country with a different population group. The bi-national collaborative study is an excellent tool to validate such genetic data.
Mucosal vaccination strategies against influenza in high risk populations
Coordinators: Andrew Potter and Carlos A. Guzman
Vaccination has proven to be the most cost-efficient preventative approach against infection. Mucosal vaccination promotes an immune response at the sites where the first line of defense against infections is laid. Thus, this approach can result in protection not only against disease, but also against infection (i.e. colonization), thereby reducing the risk of horizontal transfer from infected individuals to susceptible hosts.
Most currently available vaccines have been developed for pediatric populations and are initially tested almost exclusively in healthy young adults. This does not take into account any of the changes that occur in the immune system during the course of life. More specifically, the lack of vaccine formulations customized for the elderly represents a clear drawback for our rapidly aging populations. Diminished responses to vaccination have been widely documented in the elderly. For example, despite the fact that 70-90% of those under 65 years are protected if there is no antigenic mismatch between the specific influenza vaccine and circulating viral strains, only 30-40% of individuals over 65 are protected. Such studies provide strong evidence that dysregulation may act in concert with an overall decline in host immunity in the elderly.
The main objective of this research program is to develop and evaluate new mucosal vaccination strategies against annual and pandemic influenza with an emphasis on efficiently protecting the young and elderly and on reducing the impact of subsequent bacterial infections. To establish the characteristics of an efficacious influenza vaccine formulation, immune responses against the virus following vaccination or natural exposure will be assessed and results from different age groups (paediatric, adult and elderly) will be compared to determine correlates of protection and the mechanisms of vaccine failure. Studies will also be carried out to identify common superinfecting bacterial agents in influenza-infected patients. Based on the knowledge gained by these studies, vaccine strategies will be developed to induce the desired immune responses. Antigen delivery systems and vaccine formulations that specifically induce mucosal immunity will be developed and then will be evaluated in mice for immunogenicity, efficacy and cross-protection against other influenza strains. The most promising candidate vaccines will then be tested in ferrets, pigs, and in humanized mice. In addition, the effect of vaccination on host susceptibility to the identified superinfecting bacterial agents will also be assessed.
The members of the team have critical mass, expertise and infrastructure to carry out the proposed research program. Members in both Canada and Germany have expertise in clinical research including the handling of adult and paediatric patients with community-acquired pneumonia. Both have complementary expertise in epidemiology, immune response monitoring and clinical development of vaccines and have access to both ambulatory and hospitalized patients, as well as biobanks with patient samples. Canadian and German members have laboratories with established models for respiratory viral and bacterial infections in mice, ferrets and swine, as well as considerable experience in viral/bacterial synergy/co-infections (including genomic and proteomic analyses). Canada has state-of-the art facilities for vaccine testing in large animals up to biosafety level 3 (BSL-3), which at this present time do not exist in Germany. In addition, new BSL-3 animal facilities are currently under construction in Canada. German and Canadian partners have complementary knowledge/tools on adjuvants, antigen delivery systems, vaccine formulations, immune response monitoring and mucosal immunology. The German partners have SPF animal facilities for mouse studies up to BSL-3, as well as expertise in the generation of humanized mice. Canadian and German partners have complementary knowledge on the needs of the American and European regulatory agencies and vaccine markets. All principal investigators have participated and/or coordinated large-scale national/international projects/networks. Within the Collaboration, the team can provide advanced animal models for vaccine testing, infection studies and drug development, and there is potential synergism with other teams including the genetic determinants of host susceptibility to influenza team.
The results of this research program will increase knowledge regarding the correlates of protection against influenza infection, the main mechanisms of influenza vaccine failure, and the types bacterial infections to which people with influenza are susceptible. The program will also help to establish vaccine prototypes able to evoke desired protective immune responses, which can be further developed for use in humans.
Large-scale mutagenesis screen to identify genetic determinants of host susceptibility to influenza
Coordinators: Silvia Vidal and Klaus Schughart
Not all individuals respond in the same way to infection, and it is therefore critical to understand the causes of these differences in order to optimally prevent and treat infectious diseases.
The overall goal of this research program is to identify genes involved in host susceptibility and/or resistance to influenza A infections. The research will consist of two components: mutagenesis screens in mice and epidemiological studies in humans. Hypotheses and results will be actively exchanged between these two components. It is at this interface between mouse and human genetics, where we expect to significantly increase our current knowledge for human genetic predispositions to infectious diseases. The mutagenesis screens will take place in both countries. The mutagen, ENU, will be used to randomly mutate genes in mice and generate families carrying mutations in the genome. These families will be screened in the third generation, at the homozygous state, for enhanced susceptibility or resistance to two sub-types of influenza A virus. Additional expert laboratories in both countries will support the screen by phenotyping genetic variants and functionally characterizing the underlying genes. In addition, the functional role of these candidate genes will be tested in livestock animals, especially chicken. In the human epidemiological studies patients with strong responses to influenza A infections will be identified. Both viruses and DNA will be isolated from these patients, and possible host susceptibility genes will be investigated by a candidate gene approach, which will be based on the genes identified in the mouse screens. In addition, genes associated with infection susceptibility in humans will be investigated in mice to confirm causal genotype-phenotype relationships.
This cross-disciplinary team is comprised of experts from both experimental and clinical infection research, and will be connected to existing basic research and clinical networks in both countries. It will reach out into the European community, North America, and several other countries world-wide, including, India, China, and Russia. The results from this research will assist the work performed by other groups in the Canadian-German collaboration. For example, novel targets for intervention with small molecules may be identified, along with biomarkers to monitor host responses to vaccination.
The knowledge gained by this research will lead to new strategies for future individualized influenza diagnosis, and new strategies for the treatment of infectious diseases in humans. An additional element will be the association to veterinary institutes and research networks which help to develop prevention and treatment strategies for livestock.
Systems approach to new antimicrobial agents
Coordinators: Gerry Wright and Ronald Frank
There is a constant need for the development of novel antimicrobial agents because, over time, microbes develop resistance to currently available antimicrobial agents such as antibiotics. Historically, identification of novel antimicrobial agents has relied on the determination of MIC (the inhibition of microbe growth when chemicals are added to single types of microbes grown in a suspension). This under represents the expansive and variable genetic landscape of microbes that emerges during infection. The overall goal of the research program is to identify novel targets and antimicrobial agents using systems biology approaches, to understand the nature of their interaction and to convert the identified agents to drugs. Established and novel assays will be used to identify targets and pathways involved in microbial metabolism and virulence in vivo. This will include comprehensive analysis of gene expression in microbes (i.e. transcriptomics), comparative bioinformatics analysis across cellular networks, the use of live bacteria as biosensors and whole genome screens. Numerous and diverse sets of chemicals available in both Canada and Germany will be tested, singly or in combination, for their antimicrobial activity including products from Streptomyces and myxobacteria and extracts from other natural products. Detailed biochemical analysis of target/chemical interactions including determination of the three-dimensional structure will be performed to provide basic biological knowledge and to assist drug development.
There is dedicated infrastructure, reagents and expertise in Canada and Germany to carry out the proposed research program including the High Throughput Screening Laboratory at McMaster University in Canada and the Helmholtz Centre for Infection Research compound library in Germany. There is potential synergism with the Pseudomonas/cystic fibrosis research theme group and with the vaccine development research program. For example, targets that emerge from the virulence screen could be tested for vaccine potential.
It is essential that we continue to discover and develop new antimicrobial agents. The research program described will employ modern and novel approaches to learning more about the biology of microbes; and to the identification of new antimicrobial agents and their mechanisms of action.
Functional genomics and multidrug resistance in Pseudomonas aeruginosa
Coordinators: Joseph Lam and Susanne Häußler
Pseudomonas aeruginosa is a major opportunistic pathogen of immune-compromised hosts and individuals with cystic fibrosis (CF), and it is a significant problem due to its intrinsic antimicrobial resistance. Our working hypothesis is that environmental strains of P. aeruginosa attack the lungs of CF patients causing an initial acute infection, which evolves towards a chronic condition. The specific microbial factors as well as environmental conditions needed for bacterial persistence are unknown. The overall goal of the research program is to identify these microbial and environmental factors using functional genomics coupled with systems biology approaches. The overarching concept is that Pseudomonas modulates its transcription factors to permit the expression of genes that allow the bacterium to grow in particular environments, including the lungs of CF patients. Several P. aeruginosa strains including PA14 (a model strain), PA7 (a multidrug resistant epidemic isolate), the hypervirulent LESB58 (Liverpool epidemic strain) and six other strains whose genomes are currently being sequenced will be analysed, and the results will be compared. Analysis will include examination of gene expression at the mRNA and protein level in the different strains of bacteria grown under different conditions as well as metabolic analysis using BIOLOG and other assays. The results of this research will permit the identification the biomarkers that correlate with antibiotic resistance and the ability to grow in different environments.
The data will enhance the ongoing development of the Pseudomonas Genome Database and the SYSTOMONAS database. It is the intention of the team to integrate these databases to provide a comprehensive, interactive tool for examining the evolution and adaptation of P. aeruginosa and for revealing biomarkers that can become targets for developing novel antimicrobials.
This collaborative project takes advantage of the expertise of many of the leading P. aeruginosa researchers in both countries. Susanne Häußler, Burkhard Tümmler and Dieter Jahn in Germany share a focus of investigating the evolution of Pseudomonas aeruginosa in the lungs of patients with CF and have a collection of lung explants and sequential clinical isolates of P. aeruginosa from patients. Some of these isolates have been examined by Häußler using biofilm models to determine their phenotypic changes during this mode of growth that mimics their activities in the CF lungs. Tümmler is a leader in genome structures of P. aeruginosa and has determined the phylogeneic relationships large number of clinical isolates of bacteria. The SYSTOMONAS database was established by Jahn to facilitate the collection of a comprehensive set of data from experiments using a systems biology approach that encompasses genomics, proteomics, and metabolomics. From Canada, Joseph Lam, Roger Levesque, and Paul Roy have formed a consortium to focus on multidrug resistance in P. aeruginosa. They aim to use a systems biology approach to examine unique phenotypic features in epidemic strains and multidrug resistant strains. Lam has expertise in investigating cell surface changes in bacteria due to pathogen-host interactions, and the use of mass spectrometry for identifying components of membrane complexes in multi-drug resistant bacteria. Levesque, Hancock and Brinkman are involved in the sequencing of LESB58. In addition, Levesque provides the expertise in the use of signature-tagged mutagenesis and animal model infection for identifying essential genes for the survival of the bacteria in the host. Roy spearheaded the whole genome sequencing of strain PA7 through collaboration with TIGR. All of this expertise will serve as a platform for the proposed. There is also synergy between this theme group and the theme group developing novel antimicrobial agents, because novel targets that are identified in this proposed research could be used for screening for antimicrobial compounds using high throughput approaches.
It is anticipated that the results from this research will contribute to the understanding of the mechanisms underlying the Pseudomonas infections in immune-compromised hosts and to the development of methods to prevent and treat these individuals.
Next steps
Several future activities were discussed and planned at the meeting:
- A Consortium agreement will be drafted and will be circulated to all members of the Collaboration.
- A Canadian intellectual property expert will be chosen to work with Dr. Christian Stein from Ascenion GmbH in order to develop an intellectual property agreement.
- Meetings between members of the Collaboration and high-level representatives from German and Canadian research funding agencies are planned to inform the funding agencies about the network and its proposed research activities in an effort to secure funding.
- Dr. Emil Skamene will host a meeting of the Collaboration in Montreal in 2008. This will be an open meeting for members of the Collaboration and other interested members of the research community. The meeting will include lectures from outside experts, workshops and poster presentations. Students and other trainees will be encouraged to attend. A program committee will be struck to organize the meeting.
- To facilitate communication, an internet website will be established where reports and grant applications will be posted.
- A newsletter highlighting the activities and accomplishments of the Collaboration will be produced and circulated to members and other interested parties.
Summary
The organizers and participants were very pleased with the constructive nature of the meeting, the spirit of collegiality, enthusiasm and camaraderie among participants and the progress that was made. In a questionnaire soliciting feedback on the meeting, participants agreed that the meeting was highly successful and were pleased with the outstanding organisation and facilitation, the opportunity to interact with colleagues and the concrete work plans that were developed. See Appendix 5 for additional participant feedback from the meeting.
The projects that were discussed and developed at the meetings in Montreal and Braunschweig are innovative, ambitious and are truly collaborative in nature. The work that is planned requires the joint efforts and contributions of researchers in both countries. Working together in this manner will create a synergism and add value to the project results. The results of the research and the products that are developed through the Collaboration promise to have a major impact on the prevention and treatment of acute and chronic respiratory diseases, including an influenza pandemic, which is currently predicted to have major social and economic effects and cause numerous deaths world-wide.
Appendix 1: Members of the Meeting Organizing Committee
Co-chairs:
- Rudi Balling, Helmholtz Centre for Infection Research
- Emil Skamene, McGill University
Members:
- John Carey, Canada-Germany Science and Technology Agreement
- Abigail Forson, CIHR International Relations
- Peter Lange, Canada-Germany Science and Technology Agreement
- Carol Richardson, CIHR Institute of Infection and Immunity
- Bhagirath Singh, CIHR Institute of Infection and Immunity
- Dorothy Strachan, Strachan-Tomlinson, Process Design and Facilitation
Appendix 2: List of Meeting Participants
| Name | Institute/Company |
|---|---|
| Rudi Balling | Helmholtz Centre for Infection Research |
| Birgit Balster | Helmholtz Centre for Infection Research |
| Albert Berghuis | McGill University |
| Jan Buer | Helmholtz Centre for Infection Research/MHH |
| Dirk Bumann | Hannover Medical School (MHH) |
| Trinad Chakraborty | Uni Giessen Institut für Medizinische Mikrobiologie des Universitätsklinikums |
| Abigail Forson | CIHR International Relations |
| Ronald Frank | Helmholtz Centre for Infection Research |
| Gerald Gerlach | TiHO |
| Philip Griebel | VIDO |
| Carlos A. Guzman | Helmholtz Centre for Infection Research |
| Susanne Häußler | Helmholtz Centre for Infection Research |
| Dieter Jahn | Technical University Braunschweig |
| Joe Lam | University of Guelph |
| Andreas Lengeling | Helmholtz Centre for Infection Research |
| Roger Levesque | Laval University |
| Mark Loeb | McMaster University Henderson Hospital |
| Stefan Ludwig | Universität Münster |
| Eva Medina | Helmholtz Centre for Infection Research |
| Stefan Meuer | University of Heidelberg |
| Irina Nazarenko | German Cancer Center |
| Andrew Potter | VIDO-University of Saskatchewan |
| Carol Richardson | CIHR Institute of Infection and Immunity |
| Paul Roy | Laval University |
| Max Schobert | Technical University Braunschweig |
| Klaus Schughart | Helmholtz Centre for Infection Research |
| Bhagirath Singh | CIHR Institute of Infection and Immunity |
| Emil Skamene | McGill University Health Centre |
| Christian Stein | Ascenion GmbH |
| Burkhart Tümmler | Hannover Medical School (MHH) |
| Silvia Vidal | McGill University |
| Brian Ward | McGill University Health Centre |
| Tobais Welte | Hannover Medical School (MHH) |
| Gerry Wright | McMaster University |
| Process Consultation and Facilitation | |
| Strachan-Tomlinson, Process Design and Facilitation | |
Appendix 3: Meeting Agenda
Canadian-German Collaboration on Infectious Disease Research
Stage II Meeting
Helmholtz Centre for Infection Research, Braunschweig
Location: Forum of the Helmholtz Centre for Infection Research
March 22nd-23rd, 2007
Co-Chairs: Rudi Balling and Emil Skamene
| Thursday, March 22nd 2007 | |
|---|---|
| 08:30 | Welcome, Opening Remarks Dr. Bhagirath Singh, CIHR Institute of Infection and Immunity Dr. Peter Lange, German Co-chair for the Canada-Germany Agreement |
| 08:45 | Meeting process: approach, outcomes, introductions, report Dorothy Strachan, Facilitator |
| 09:15 | Genesis, objectives and goals of the Canadian-German Collaboration on Infectious Disease Research Dr. Rudi Balling, Dr. Emil Skamene |
| 09:30 | The Canadian "Pandemic Preparedness Research Initiative" Dr. Bhagirath Singh, CIHR Institute of Infection and Immunity |
| 09:40 | An Introduction to "The German Flu Research Network" Dr. Stefan Ludwig, University of Muenster |
| 09:50 | Discussion |
| 10:00 | Process overview for theme group discussions: Dorothy Strachan Group worksheet: title, team members, objectives, descriptive overview, added value for this project to be carried out by a Canadian-German team, main parts of the project, rough estimate of timelines, potential milestones, Canadian-German complementarity, interactions with other projects/components/mechanisms, key issues requiring further discussion |
| 10:10 | Break |
| 10:30 |
Theme group action planning:
|
| 12:00 | Lunch |
| 13:00 | Process for Presentations on Theme Group Results: Dorothy Strachan |
| 13:05 |
Theme group presentations (Each presentation: 10 minutes; Q and A: 10 minutes)
|
| 14:10 | Break |
| 14:30 |
|
| 15:45 |
Plenary discussion: Dorothy Strachan
|
| 16:30 | Intellectual Property - Dr. Christian Stein |
| 17:00 | Agenda for tomorrow |
| 17:10 | Organizing Committee meeting |
| Friday, March 23rd, 2007 | |
| 08:30 | Agenda overview: Dorothy Strachan IP discussion: plenary summary of key points |
| 09:00 | Theme group meetings to refine and complete Thursday's teamwork |
| 10:00 | Break |
| 10:15 |
Group reports: (5 minutes each group)
|
| 10:45 |
Commentary: an Integrated Approach - the Synergy of 5 Teams
|
| 11:45 | Summary and next steps: Rudi Balling and Emil Skamene |
Appendix 4: Detailed Research Proposals in Strategic Priority Areas
Genetic and environmental determinants of immune response to inactivated influenza vaccination
Project team members
-
From Canada
Coordinator: Mark Loeb
Other team members: Emil Skamene, Rafick Sekaly, Erwin Schurr -
From Germany
Coordinator: Stefan Meuer
Other team members: Jan Buer, Dolores Schendel, Rudi Balling
Objectives
The main goal of this research program is to identify the determinants of response to inactivated influenza vaccine in different age groups. Specific objectives are to
- Determine gene expression profiles associated with protective antibodies
- Determine genotypes associated with this response
- Identify environmental co-variates implicated in influenza specific vaccine response.
Project Description
- Develop three different cohorts of participants on the basis of age (5 to 15 years; 20 to 50 years; > 65 years) who will be vaccinated with influenza inactivated vaccine.
- Obtain serology (HAI) at baseline and at 4 weeks post vaccination to determine vaccine response
- Obtain whole blood for gene expression profiling at pre-determined intervals (to be determined through a pilot study)
- Measure demographic and other participant-specific characteristics
- Model the vaccine response on aforementioned variables
Work Packages
- Patient populations: 1) Children participants in an clinical trial in Prarie provinces (founder population - Hutterites), healthcare workers (age 20-50 years), hospital volunteers (> 65 years)
- Immune phenotyping platform (Germany/Canada)
- Genotyping platform (Canada)
Timelines and Milestones for Work Packages
Pilot project: October 2007 to September 2008
Patient enrolment: October 2008 to November 2009
Integrated Approach
Canadian and German Team Complementarities
- Each country will contribute to the participant population
- Gene expression platform will be based in Germany, genotyping in Canada
Contribution of this Team to the Canadian/German FIRE & ICE Network
- Strong potential for synergy with the vaccine development group who will assess immune response to influenza vaccination in animal models
- Synergy with the group assessing genetic susceptibility to influenza in animal models
Contributions of Other Canadian/German FIRE & ICE Network Teams to this Team
- Candidate genes from the animal models will be important to integrate into our plans for genotyping
- Our findings can potentially be validated by the animal vaccine group
Other Components/Mechanisms/Activities/Institutions that Could Contribute to the Project
- e.g. Pandemic funding CIHR, CRI, Genome Canada
Implementation
Opportunities and Challenges to Support Next Steps and Longer Term Implementation
- Extension of pre-existing activities
Mucosal vaccination strategies against influenza in high risk populations
Project team members
-
From Canada
Coordinator: Andrew Potter (VIDO)
Other team members: Philip Griebel (VIDO ), Brian Ward (McGill Univ) -
From Germany
Coordinator: Carlos A. Guzman (HZI)
Other team members: Gerald Gerlach (TiHo), Tobias Welte (MHH, absent)
Objectives
- Develop new mucosal vaccination strategies against endemic and pandemic influenza
- Establish approaches to achieve efficient protection in young and elderly individuals
- Develop models in mice and pigs for superinfection of influenza infected animals with Streptococcus spp. and other bacterial pathogens
- Evaluate the effect of vaccination on the impact of infections caused by superinfecting agents
Project Description
- assess immune responses after infection and vaccination in different age groups (i.e., paediatric, adults, elderly) to define better correlates for protection, to dissect the mechanisms for vaccine failure and to establish the pre-requisites for an efficacious influenza vaccine
- perform epidemiological studies to determine the main bacterial superinfecting agents in influenza-infected patients
- develop mucosal vaccination strategies to evoke appropriate humoral and cellular immune responses in the elderly and the young after mucosal immunization
- perform a comparative evaluation in different experimental animal models (mice, humanized mice, pigs and ferrets) of the immunogenicity and efficacy of vaccine formulations to select the most promising candidates for clinical development
- establish an experimental animal model of superinfection to assess the influence of vaccination with respect to subsequent bacterial infections
Work Packages
WP1: Evaluate immune and clinical responses after infection and vaccination:
- assess immune responses after infection and vaccination in different age groups (i.e., paediatric, adults, elderly)
- better define the correlates for protection
- dissect the mechanisms for vaccine failure
- perform epidemiological studies to identify superinfecting agents in influenza-infected patients:
WP2: Develop vaccination strategies to evoke desired immune responses:
The specific type of immune responses will be defined according to the outcome of WP1. Particular emphasis will be given at the establishment of vaccination strategies able to promote mucosal immune responses (i.e., due to their impact in blocking flu transmission)
- identify antigen delivery systems able to trigger adequate responses
- select adjuvants improving immune responses in elderly and young animals
- develop vaccine formulations stimulating systemic and mucosal immune responses
WP3: Evaluate the immunogenicity and efficacy of the optimized formulations and strategies in experimental animal models:
- assess the immunogenicity of the selected formulations in mice
- confirm the efficacy of the best candidates in ferrets
- assess the immunogenicity of the most promising formulations in pigs
- assess the immunogenicity of the most promising formulations in humanized mice
- assess the influence of vaccination in host susceptibility to a superinfecting bacterial agent
In the context of the WP we will also evaluate the capacity of the most promising vaccine formulations to promote cross-protective responses (e.g. determination of HA-inhibitory antibodies and efficacy studies).
Expected outcomes:
- Knowledge about the main mechanisms of vaccine failure in the young and the elderly
- Identification of main superinfecting bacterial pathogens
- Better correlation markers for protection
- Identification of antigen delivery systems and adjuvants able to evoke well-defined immune responses
- Comparative knowledge on the immune responses stimulate in mice, humanized mice and pigs after vaccination with well-defined vaccine formulation
- Selected vaccine prototypes able to stimulated desired immune responses for clinical development
Timelines and Milestones for Work Packages
Timing for overall project startup: preliminary work for selection of most suitable vaccination strategies and immune modulators have already started using intramural funds. The same is valid for the development of critical experimental models and the identification of suitable patient cohorts. The major joint efforts will start as soon as seed money is secured for the initial studies.
Estimated timeline for overall project completion: 3 years
Milestones and timelines for main parts of projects:
Component WP1:
Depends to some extend on the severity of the annual influenza outbreaks
- Complete the data collection including two influenza seasons (18 months effort, starting with the influenza season)
- Finalize data analysis (month 24)
- Complete study on superinfecting agents (month 36)
Component WP2
- Primary screening immunization strategies able to promote immune responses in young and aging mice (month 18)
- Optimizing immune responses in young and aging animals (month 30)
Component WP3
- Immunogenicity and efficacy of 1st generation candidates (month 24)
- Immunogenicity and efficacy of 2nd generation candidates (month 36)
Integrated Approach
Canadian and German Team Complementarity
The members of the consortium have critical mass, expertise and infrastructure to address the development of vaccines against viral and bacterial agents causing respiratory infections. Partners from both Canada (McGill) and Germany (MHH) have expertise in clinical research including the handling of adult and paediatric patients with community-acquired pneumonia. Both counterpoints have complementary expertise in epidemiology, immune response monitoring and clinical development of vaccines. Furthermore, they have access to both ambulatory and hospitalized patients, as well as biobanks with patient samples (eg: German Competence Network on community-acquired pneumonia (CAP-NET). Canadian (VIDO, McGill) and German (MHH, TiHo) laboratories have established models for respiratory viruses and bacterial infections in mice, ferrets and swine as well as considerable experience in viral/bacterial synergy/co-infections (including genomic and proteomic analyses). Canada (VIDO) has state-of-the art facilities for vaccine testing in large animals up to BSL-3, which are currently lacking in Germany. German (HZI) and Canadian (VIDO, McGill) partners have complementary knowledge/tools on adjuvants, antigen delivery systems, vaccine formulation, immune response monitoring and mucosal immunology. The German partners (HZI) have SPF animal facilities for mouse studies up to BSL-3, as well as expertise in the generation of humanized mice. Canadian and German partners have complementary knowledge on the needs of the American and European regulatory agencies and vaccine markets. All principal investigators have participated and/or coordinated large scale national/international projects/networks (Gates, Genome Canada, EC, etc).
Contribution of this Team to the Canadian/German FIRE & ICE Network
- We can provide advanced animal models (conventional and humanized mice, pigs) for vaccine testing, infection studies and drug development
- Generation of complementary data sets with the project addressing the identification of genetic determinants of host susceptibility to influenza and response to vaccination. In this particular context synergistic interactions are foreseen.
- Model of superinfection for genetic susceptibility studies
- Screening tests for small molecules with adjuvant activity
Contributions of Other Canadian/German FIRE & ICE Network Teams to this Team
- Synergistic interactions are foreseen with the project addressing the identification of genetic determinants of host susceptibility to influenza and response to vaccination.
- Expertise on mucosal immunity (above-mentioned project)
- DNA archiving
- Small molecules with adjuvant activities
Other Components/Mechanisms/Activities/Institutions that Could Contribute to the Project
- Rafick Sekaly (immune monitoring)
- German Influenza Network
- CFIA (Canadian Food Inspection Agency) BSL3 animal facilities
- CAP-NET
- Canadian Pandemic Preparedness Initiative
Implementation
Opportunities and Challenges to Support Next Steps and Longer Term Implementation
- AP to contact Richard Harland at Novartis re: potential partnership and funding
- LOI Canadian Pandemic Preparedness Initiative
- CAG contact Crucell and associated companies
- Others: Bill and Melinda Gates, CIDA, etc.
Large-scale mutagenesis screen to identify genetic determinants of host susceptibility to influenza
Project team members
-
From Canada
Coordinator: Silvia Vidal
Other team members: Emil Skamene, Sal Qureshi, Mark Loeb, Earl Brown, Philippe Gros, Erwin Schurr -
From Germany
Coordinator: Klaus Schughart
Other team members: Eva Medina, Stephan Ludwig, Thorsten Wolf/Brunhilde Schweiger, Peter Stäheli
Objectives
Scientific objectives
- Identify genetic regions or gene loci involved in resistance and/or susceptibility to influenza A infections …
- Using mouse model systems to understand host-pathogen interactions in humans and livestock
- Characterize host phenotype
- Characterize biochemical pathways
- Characterize viral virulence factors involved
- Vlidate finding in humans and livestock
Other objectives
- Exchange of students, reagents, technologies, mouse strains and mutants
- Generating a common database (integrated database)
- Seed for world-wide effort
Project Description
- ENU-screen in C57BL/6J mice, using H1N1 & H7N7 strains
- primary phenotyping of adult mice (survival, viral loads)
- secondary phenotyping (cell-autonomous response, immuno-phenotyping of innate and adaptive immune response)
- Mapping of mutation, fine mapping, and cloning of underlying gene mutation
- Functional analysis of host genes and viral factors involved
- Validate for human and livestock orthologous regions and genes
- Valorization and exploitation of the newly generated mouse models for prognosis and risk factors (genetic & biomarkers) in human and livestock, work our mouse-human differences and common gene networks/pathways
Work Packages
WP1:
- prepare and characterize common virus stocks
- establish common interactive database
- set up ENU mutagenesis and G3 families
- establish SOPs for infection and phenotyping, infection model, primary & secondary phenotyping methods and recording
WP2:
- Screen mutagenized G3-families
WP3:
- Mapping and sequence analysis (candidate regions in Mb-size and candidate genes)
- low resolution mapping
- high resolution
- candidate region sequencing
- identification of candidate gene
WP4:
- Validation of candidate gene
- overexpression and knock-down in cell culture, transgenic, KO
WP5:
- Functional analysis of susceptibility / resistance gene(s)
- protein-protein interactions in context of viral infection
- virus life cycle & virulence
- biochemical analysis
- cellular analysis (pathway, etc.)
- expression analysis
- network analysis
- in vivo function (immune system, organ homeostasis, etc.)
WP6:
- Valorization of mouse model
- Relevance of susc/res gene(s) in context of other infections
- Identify biomarkers in serum proteome & cellular phosphor-proteome (to translate to human and livestock)
- Vaccine response in mouse mutant (to translate to human and livestock)
- Identify orthologous genes in human (e.g., patients with severe susceptibility to infections, patients with severe complications associated with FLU infections) and livestock to look for associations with infection susceptibility / resistance
- Mouse human comparison (common & different pathways towards the creation of humanized mice for infection susceptibility & development for new therapies in humans)
Timelines and Milestones for Work Packages
Timing for overall project startup: Mid- 2007 for grant application to CIHR and NGFN
Estimated timeline for overall project completion: five years
- WP1: months 0-9
- WP2: months 9-48
- WP3: months 18-60
- WP4: months 24-60
- WP5: months 36-60
- WP5: months 36-60
Integrated Approach
Canadian and German Team Complementarity
-
Expand virus subtypes
H1N1 Canada
H7N7 Germany -
Secondary phenotyping and expertise for it
innate response Canada
adaptive response Germany
cell-autonomous Germany -
Genotyping Canada
Sequencing Germany -
Valorization
serum proteome Canada & phospho-proteome Germany
additional virus strains (NRF in Germany, Strain collection in Canada) -
Building on additional complementary genetic approaches, esp. complex trait analyses
complementary mouse resources Germany (IS, RIS), Canada (IS, RCS) -
Infrastructure to work with virulent strains
BSL3 in Canada
BSL3 in Germany after 2008 -
Veterinary groups and expertise associated
FLI, TiHo in Germany
VIDO in Canada
Contribution of this Team to the Canadian/German FIRE & ICE Network
- Target genes & pathways for improved innate host resistance and efficacy of vaccination
- Generate hypotheses for genetic determinants of vaccine/immunization response
- Targets for intervention with small molecules
- Biomarkers to monitor host responses to vaccination or virus infections (new strategies for vaccination, genetic determinants of vaccine response)
Contributions of Other Canadian/German FIRE & ICE Network Teams to this Team
- Bring in the human perspective
- Candidate regions and genes from human studies (genetic determinants of vaccine/immunization response)
- Small molecules to analyse host-pathogen interactions (chemical biology)
Other Components/Mechanisms/Activities/Institutions that Could Contribute to the Project
- FluResearchNetwork (Zoonoses-Consortium, Germany - final approval expected in May07)
- GeNeSys (Complex Trait consortium, Germany)
- EuroFlu (HPAIV biology, EU FP6, Germany)
- FluInnate (Innate response to HPAIV, EU FP6, Germany)
- Virgil (viral resistance mechanisms on HBV, HCV, Flu, EU FP6, Germany)
- Canadian genetic diseases network (Canada)
- Influenza-Prepareness Task Force (Canada)
- Recombinant Congenic strain panel (Canada)
- Montreal Genome Centre (Canada)
- LOI application for team grant CIHR (approval expected May 07, full application due in Sep 07)
- LOI for NetGrant "Prepareness for influenza" (due June 07, full application Jan 08)
Implementation
Opportunities and Challenges to Support Next Steps and Longer Term Implementation
- NGFN3 & CIHR (deadline NGFN 21.7.07, CIHR Sept. 07)
- Genome Canada
- NIH
Systems Approach to New Antimicrobial Agents
Project team members
-
From Canada
Coordinator: Gerry Wright
Other team members: Eric Brown, Albert Berghuis -
From Germany
Coordinator: Ronald Frank
Other team members: Dirk Bumann, Trinad Chakraborty
Objectives
Historically antimicrobial research has been driven by in vitro determination of MIC. This under represents the expansive and variable genetic landscape that emerges during infection. The differences that emerge between in vitro and during infection are exploitable in new screens for antimicrobials.
- Apply 21st century biology to improve on existing 19th century assays e.g. systems biology, in vivo infection biology
- Use chemical diversity available from Canadian and German partners,
- Follow-up lead-target pairs with mechanistic analysis, detailed biochemical research and three-dimensional structural analysis to inform structure-activity relationships as basis for medicinal chemistry
- Validation in animal models
Project Description
- Use established and create new assays to identify and screen new and old target proteins and pathways in in vivo metabolism and virulence
- Use system biology approaches to explore novel compound combinations and identify target-compound interactions as well as off-target interactions (Tox, resistance, metabolism)
- Convert leads to drugs
Work Packages
- Assay development - models to high-throughput screens
- Novel chemistry
- Downstream analysis of compound-target interactions
Timelines and Milestones for Work Packages
Timing for overall project startup: 18 months
Estimated timeline for overall project completion: 5 years
Milestones and timelines for main parts of projects:
Component WP1: Assay development
- Cell-based antibiotic resistance and susceptibility tests (in place)
- Pan genome based transcriptome studies (CA-MRSA; Pseudomonas)
- Comparative bioinformatic analysis across cellular networks
- Whole cell live bacteria as biosensors
- Non-obvious chemical combination screens
Component WP2
- Myxobacterial natural products (in place)
- Purification of natural products from extracts (ongoing)
- Combinatorial expansion of hits that emerged from assays
Component WP3
- Target identification using whole genome screens
- Production and verification of targets
- Biochemical analysis of target compounds interactions including three dimensional structure
Integrated Approach
Canadian and German Team Complementarity
- Dedicated infrastructure and expertise in Canada and Germany (e.g. HTS Lab at McMaster; HZI compound library)
- Novel cellular assays - Canada (Antibiotic resistance; genome scale cellular arrays for target identification); Germany ( Pan-genome transcription arrays; fluorescence-based biosensors)
- Novel chemistry - Canada (Novel collection of Streptomyces extracts) Germany (Myxobacteria extracts and metabolites; Natural product inspired combinatorial chemistry)
- (medicinal chemistry (HZI), structure and mechanism (Canada)
Contribution of this Team to the Canadian/German FIRE & ICE Network
- Synergism with Pseudomonas/CF project
- Synergy with the vaccine development project/animal models
- Targets that emerge from the virulence screen can be tested for vaccine potential
- New assays to test antivirals (flu)
- Including assays of small molecule adjuvants
Contributions of Other Canadian/German FIRE & ICE Network Teams to this Team
- Novel targets from Pseudomonas projects
- Potential models for infection/susceptibility studies
Other Components/Mechanisms/Activities/Institutions that Could Contribute to the Project
- Chemical Biology Network in Canada/Germany
- Structural Genomics Network in Canada
- Pathogenomics Network in Germany/EU
- National Genome Research Network (NGFN) in Germany
- German HEPATOSYS network
- Canada CRI
- EU Innovative Medicine Infrastructure
Implementation
Opportunities and Challenges to Support Next Steps and Longer Term Implementation
- Identify experts to incorporate ADME-Tox mechanism
Functional genomics and multidrug resistance in Pseudomonas aeruginosa
Project team members
-
From Canada
Coordinator: Joe Lam
Other team members: Roger Levesque (Laval U), Paul Roy (CHUL, Laval U), Bob Hancock, (UBC), Fiona Brinkman (SFU), Keith Poole (Queen's U), Howard Ceri (UC), Christine Bear/Felix Ratjen (SCH, Toronto), André Cantin (Sherbrooke U) -
From Germany
Coordinator: Susanne Häußler
Other team members: Burkhard Tümmler (MHN), Dieter Jahn (TUB), Max Schobert (TUB), Lothar Jaensch (HZI)
Objectives
- Functional genomics of multidrug resistant strain (PA7), epidemic strain (LESB58), PA14 (most abundant occurrence, 15% of all strains)
- Focus on the dominant clones in the population
- Developing SYSTOMONAS database for world-wide access - to integrate all data from the PSEUDOCAP, proteomics, metabolomics, interactomics, transcriptomics, phenotyping (in vitro, ex vivo, in vivo)
Project Description
- Completing functional genomics, PA14 as a model strain, PA7 (multidrug resistant), LESB58 (highly contagious and multidrug resistant)
- Integrative Biology - genomics (islands), proteomics, metabolomics, interactomics, transcriptomics, mutant phenotype (in vivo, ex vivo, and in vitro), natural diversity (microbial ecology) - collectively data collected to establish SYSTOMONAS database
- Knowledge gained on the emergence of multidrug resistance (MDR) will be fed into SYSTOMONAS to first address the impact of growth and metabolism on MDR via a System Biology Approach
- Resistance phenotype, drug-target phenotypes (merge with Microbial Virulence and Antibiotic Resistance theme-group)
- Diversity of large genomic islands in the P. aeruginosa populations as a means for emergence of multi-drug resistance and horizontal transfer
Work Packages
- PA14 chips by Affymetrix, research co-operation from several institutions, chip should cover core genome
- 2nd chip to cover genomic islands of all major types of Pseudomonas aeruginosa
- Phenotyping analysis - BIOLOG and other algorithms (assays)
- In vivo selection of virulence-associated genes, plus or minus antibiotic pressure
Timelines and Milestones for Work Packages
Overall project start time: within 1 year
Estimated timeline for overall project completion: 3 years
Milestones and timelines for main parts of projects:
Component A: Affymetrix chips of PA14
- Chip of core genome - 6 months after start
- Metabolic phenotyping - 18 months after start, priority given to unknown ORFs
Component B: genomic island chips
- Sequencing of genomic islands in the major clones - BAC clones, 18 months
- Chip - 1st and 2nd editions, 6 and 18 months, respectively
- Natural diversity screening - 3 years
Component C: Drug-resistance genes and targets
- In vitro screening - 1 year
- In vivo screening - 1 year, (200 animals, handle almost 10,000 mutants)
- Epidemiology - 3 years
Component D: Systems Biology
- Integration of SYSTOMONAS (Germany) and PSEUDOCAP (Canada) - 2-phase approach, initial start almost immediately, refinement 6 months after start and continuing
- Extension of SYSTOMONAS, concept of integration of all the various experimental data
Integrated Approach
Canadian and German Team Complementarity
- Provide added value by building on the long-standing strengths and the focus of P. aeruginosa and cystic fibrosis research teams in both countries
- Added value to Pseudomonas aeruginosa genomics and system biology
- Integrating existing databases and bioinformatic infrastructure
- Exchange of complementary expertise and of trainees
- Identification of anti-bacterial targets relating to drug-resistance (merging with Microbial Virulence and Antibiotic Resistance Theme Group)
- Support for examining host response, cftr-/- mice, and inflammation expertise are contributed by Christine Bear/Felix Ratjen, and André Cantin
- Complementarity to search for the genetic modifiers of host response to P. aeruginosa in the whole CF patient population (HSC Toronto, J. Zielenski) and the European Cystic Fibrosis Twin and Sibling Study (MHH, KU Leuven)
- Development of novel geno- and patho-typing devices for diagnostics - commercial potential
Contribution of this Team to the Canadian/German FIRE & ICE Network
- Synergism with Microbial Virulence and Antibiotic Resistance Theme Group, testing novel compounds in vivo using animal model and in vitro biofilm models.
Contributions of Other Canadian/German FIRE & ICE Network Teams to this Team
- We could exploit: assay systems developed by the Microbial Virulence and Antibiotic Resistance Theme Group including:
- Cell-based antibiotic resistance and susceptibility test systems
- Pan-genomic transcription studies
- Whole cell live bacteria as biosensors
- Comparative bioinformatics analysis across cellular networks
- Potentially we could derive benefit from the expertise of the mouse genetics research theme
Other Components/Mechanisms/Activities/Institutions that Could Contribute to the Project
- We can derive from the experience of the working concept and intellectual property sharing agreement established in the Canadian Bacterial Diseases Network.
- National database of Canadian cystic fibrosis patients developed by Mary Corey, Toronto Hospital for Sick Children
- Qualitaetssicherung Mukoviszidose (German CF patient registry)
Implementation
Opportunities and Challenges to Support Next Steps and Longer Term Implementation
Funding source:
- NSERC Collaborative Health Research Projects program - Notification of Intent (NOI) to be submitted by May 1, full application by Oct. 1, to fund the projects of Canadian researchers from the different institutions, ~$150k to $250k per year for up to 3 years. (Joe Lam will prepare the NOI for submission)
- Canadian CF Foundation - full operating grant application by Oct. 1, targeted for creating a STM library of strain PA14, followed by libraries for PA7 and other predominant clones (from CF clinical isolates), ~$70k to support 1 technician and supplies. Roger Levesque will be the PI of this application and Paul Roy will be a co-applicant.
- German CF Foundation - LOI by April 10, if approved by June, full application by Oct 1: analysis of genomic islands in dominant clones (sequence, bioinformatics, MDR loci), EUR 100k for 1 year technician and sequencing of islands ORFs (To date, a LOI has been submitted by B. Tümmler).
- Ontario - International Strategic Opportunities Program (ISOP) - ~$150k for up to 3 years. (Total funding per research collaboration initiative will normally not exceed $150,000 over three years. The program will generally fund up to 50% of the eligible costs on a one-time basis, with the balance coming from non-Ontario government sources. In this case, perhaps the committed funding that has been secured by the German collaborators might be used as a collateral match.) No pre-set deadline date for application.
- German Research Foundation (MS, SH, BT) system biology of MDR and biofilm formation phenotypes: intraclonal evolution in the dominant clones: 180k EUR per year for up to 3 years
- Genome Canada - requires matching fund, Andy Potter suggested someone should contact Bob Brunham's LOI entitled "Emerging Infections Diseases" for this group to become a partner of.
- Mechanism of application as a bilateral program, and not individual theme projects
Appendix 5: Feedback on the Meeting from Participants
Participants rated the success of the meeting from their perspective as follows:
| Not Successful | Somewhat Successful |
Successful | ||||
|
| ||||||
| 1 | 2 | 3 | 4 | 4.5 | 5 | |
| (9) | (2) | (16) | ||||
| n = 27; Average = 4.6 | ||||||
Participants indicated that they liked the following the most:
- Organization and facilitation (n = 21), e.g.,
- excellent location, great hosts/organizing team/facilitation
- the chance to break in groups and reconvene for discussion; discussion templates prepared in advance
- the meeting was focused, well planned and organized, and on time; now I know what a facilitator can do.
- Interactions with colleagues (n =17), e.g., the
- open discussions and the excellent non-competitive atmosphere for synergistic work
- opportunity to network with and meet new colleagues from a wide variety of research areas
- spirit of collegiality, enthusiasm and camaraderie among participants.
- Good outcomes (n = 12), e.g., we
- established a strong Canada-German collaboration/network
- identified opportunities to combat infectious disease
- set up concrete work plans.
- The obvious care taken in the choice of venues, events, dinners, etc. (n = 3)
Participants indicated that they liked the following the least:
- Time pressures (n = 6), e.g., there was not enough time
- for breaks
- in breakout discussion sessions (but we handled it well)
- to discuss research projects in depth.
- The difficulties we had identifying feasible funding strategies. (n = 4)
- Services (n = 2), e.g.,
- there was too little coffee on the first day
- wireless didn't work in the forum.
- The weather. (n = 2)
- Lack of interaction among groups.
4. Additional comments:
- At the next meeting:
- include funding agency, policy people and more clinically-oriented colleagues as discussion partners
- mix groups more to synergize ideas.
-
It seems that there are two distinct projects - influenza and bacteria - that have only tangential overlap.
-
Common agenda should not just cover flu and cystic fibrosis.
-
I did not expect such a productive and results-oriented meeting. Bravo!
-
I will recommend having a "facilitator" for our internal meetings.
-
This project looks very positive; it has a serious chance to succeed - let's keep meeting like this.