Using genomics to understand pathogen-host interactions and disease prevention.
The prevention and treatment of infectious diseases presents similar challenges in humans and animals. The “disease triangle”, which conceptualizes the interaction between the host, pathogen, and the environment, is a framework to describe how a microbial pathogen enters, establishes a foothold in, and is eventually eliminated (in most cases) from the host. Despite the variety of infectious diseases and number of potential hosts, there are common themes in the way a bacterial pathogen establishes itself in the host (call pathogenicity), and the way a host responds to the early stages of infection (called the innate immune response). These initial interactions have important ramifications on the eventual outcome, which can range from a rapid clearance, a mild or serious infection with recovery and long term specific immunity, a hyperactive immune response causing serious damage to the host, or an inadequate immune response resulting in death.
The initial step in the pathogen-host interaction most often occurs on mucosal membranes lining the respiratory, gastrointestinal and urinary tracts. The overall objective of the Functional Pathogenomics of Mucosal Immunity (FPMI) project was to increase understanding of the interaction of bacteria with mucosal tissues of human, avian, and bovine hosts. At the core of the project was the analysis at the genetic level of the innate immune responses when encountering bacteria, of when stimulated by purified bacterial molecules. This knowledge could then be used to design and test novel strategies to prevent or treat infectious diseases. This includes advanced vaccine design and tailoring immune responses early in the infection process. The results attained are enabling the rational development of new and effective strategies for improving human health, animal productivity and the economic viability of the livestock industry through enhanced animal welfare and food safety.
Through the development of in human and bovine cell culture models, and bovine and chicken infection models, the FPMI team identified several hundred genes involved in the innate immune response in humans, cattle, and chickens. Genes of interest were further analysed in cell culture models to determine their response during infection, and to be used as markers for testing new therapeutic compounds which enhance innate immune responses. Bovine and chicken model infections were also established to validate host-pathogen responses in vivo. These findings aided in the development of novel therapeutics called immune modulators, and selected compounds were licensed for preclinical development by industry partner and co-funder, Inimex Pharmaceuticals (Vancouver, BC).
To handle the high volume of data throughput, a web-based, semi-automated, open source pipeline “ArrayPipe” was developed by our bioinformatics group at Simon Fraser University for the initial pre-processing of microarray data (http://koch.pathogenomics.ca/cgi-bin/pub/arraypipe.pl). This project also led to the development of InnateDB, a publicly accessible database for innate immunity research, which users can search for particular genes or proteins of interest, their associated interactions and pathways, and conduct downstream data analysis. InnateDB currently includes over 18,000 manually curated interactions.
– New knowledge was gathered about genes involved in the immune response to infections in both human and bovine species, leading to new targets for development of therapeutics.
– New compounds were developed which have the ability to treat microbial infections by boosting the host innate immune response.
– This project employed 200 person years equivalent.
– Presented 74 public lectures, participated in 9 public forums.
– Four new provisional patents filed.
– ArrayPipe (www.pathogenomics.ca) our open source microarray analysis tool averaged 80 unique web hits per month and SFU started development of two annotation databases for innate immunity interactions, InteractDB and InnateDB, to facilitate downstream data analysis.
– Started new collaborations with researchers from Cuba and Ireland to expand understanding of the interaction between bacterial pathogens and immunomodulators on host cells from several species.