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The Genome Canada Competition II FPMI Project has concluded. These pages will be maintained for archival purposes. For information on the Competition III Pathogenomics of Innate Immunite (PI2) Project, please visit www.pathogenomics.ca

 

 

 

This project is supported by Genome Prairie, Genome British Columbia and Genome Canada, a not-for-profit organization which is leading Canada's national strategy on genomics with  $ 600 million in funding from the federal government.

 

 

 

Functional Pathogenomics of Mucosal Immunity (FPMI)


Overview

Mucosal immunity represents the broad range of host defenses that prevent the attachment and invasion of infectious disease agents at the body surfaces of the respiratory, digestive, and reproductive tracts. The Functional Pathogenomics of Mucosal Immunity (FPMI) program is utilizing the power of genomics and bioinformatics to increase current understanding of how mucosal immunity to infectious agents operates, and how it may be enhanced to enable the rational development of new and effective strategies for improving human health, animal productivity and welfare, food safety and the economic viability of the livestock industry in the Prairies, Canada and elsewhere.

Unlike other efforts in this field, the FPMI program is investigating mucosal immunity using genomics approaches in a wide range of hosts, including humans, chickens and cattle, and thus straddles the fields of agriculture and health. This permits very broad conclusions to be made about the mechanisms of immunity in these hosts, as well as measures that will enhance immunity. The program addresses important social and financial issues since infectious diseases cost the livestock industry billions of dollars annually, while human infectious diseases cause one third of all deaths on the planet and are the major cause of loss of productivity in our society. 

The FPMI project team brings together the internationally recognized livestock health research excellence of the Vaccine and Infectious Diseases Organization, the R & D capacity at Inimex Pharmaceuticals, and a network of world-class genomics, bioinformatics, microbiology and immunology research experts at the University of British Columbia, the University of Saskatchewan, Simon Fraser University, and elsewhere in Western Canada, who have been involved in major scientific advances in understanding host:pathogen relationships.

 

 

Objectives

The overall objective for the FPMI program is to provide new information about the processes of disease and innate immunity to microbial pathogens. The results of this research program will enable researchers to gain an increased understanding of how the mucosal surfaces of bovine, chicken and human hosts respond to the presence of infectious agents, and to the adjuvants, immuno-modulators and vaccines designed to combat these agents.

Specific Aim 1 – to characterize, using epithelial and lymphoid cells, the host gene expression responses to pathogens including the development of microarray platforms

Specific Aim 2 – to generate full genome chicken microarray

Specific Aim 3 – to characterize host gene expression responses in enteric and respiratory animal infections

Specific Aim 4 – to determine the influence of adjuvants, immuno-modulatory agents including antimicrobial peptides, and vaccines on host gene expression

Specific Aim 5 – to study the influence of pathogen genetics on the host response

 


Progress to date


Gene expression studies in host cells were conducted using a bovine microarray developed at Pyxis, based on a library of 7000 cDNAs, and human microarrays based initially on 21,000 oligo set from Qiagen and recently a 19,000 cDNAs set. This data is being compiled in a database of human, bovine and chicken genes regulated in isolated primary cells and/or cell lines by exposure to various bacterial and viral pathogens. To handle the high volume of data throughput, a web-based, semi-automated, open source pipeline “ArrayPipe” has been developed by our bioinformatics group at Simon Fraser University for the initial pre-processing of microarray data. Clustering analysis on potential co-regulated genes is starting to indicate key genes and pathways to target for future studies. Common sets of experiments being conducted at both the Vaccine and Infectious Diseases Organization and the University of British Columbia will help us examine the interaction of bacterial pathogens and immune-modulating compounds with human and bovine monocytes, for broad comparative genomics analyses. Bovine and chicken model infections have been established to validate host-pathogen responses in vivo and are permitting functional genomics analyses in infections of substantial economic importance.

Understanding the influence on host gene expression of immunomodulatory agents, including antimicrobial peptides, adjuvants and vaccines, will help us to develop novel compounds for enhancing the innate and/or adaptive immune response, and/or to reverse the harmful effects of an excessive inflammatory response. Our data has demonstrated the ability of natural and designed host defence peptides to protect against both Gram negative and Gram positive bacterial infections in mice. Studies of a broad range of such peptides and their effect on gene expression of host cells has revealed a pattern of gene expression that appears to reflect the ability of these peptides to protect against infection in mouse infection models.

We have also constructed a library of 10,000 random Pseudomonas aeruginosa lux transposon mutants, and sequencing is completed on 3200 PCR products. These results indicate that the library contains knockout mutations in about 50% of non-essential P. aeruginosa genes, two thirds of which are lux reporter fusions. These mutants are being screened for phenotypic characteristics to further our understanding of gene expression and regulation in pathogenesis.


   



 

 


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© 2002 Functional Pathogenomics of Mucosal Immunity . . . A Genome Prairie Project