Program Overview

The 5-year-old Host Genetics and Prion Disease program (HGPD) concentrates on the infectious agents and host responses of Transmissible Spongiform Encephalopathies (TSEs, also known as prion diseases). TSEs comprise a number of lethal transmissible neurodegenerative conditions affecting both humans (Creutzfeldt-Jakob disease) and animals (bovine spongiform encephalopathy, BSE, in cattle; scrapie in sheep and goats; and chronic wasting disease, CWD, in deer and elk). These rare diseases are widely believed to be caused by unconventional, virus-like infective agents composed largely or entirely of a misshapen host protein.

The diseases themselves are characterized by:

• possible recurrent spontaneous origin, via misfolding of a normal host protein;

• long asymptomatic incubation periods (years to decades); wholly intractable clinical course;

• uniformly fatal outcome;

• lack of antemortem, especially preclinical, diagnostic tests;

• sporadic, heritable and infectious forms with overlapping features;

• many affected farmed species – sheep, cattle, goats, elk, deer;

• endemic persistence – no TSE has ever been conclusively eradicated, even locally; and

• worldwide shortage of scientific and technical expertise.

Given the unparalleled challenges posed by the characteristics of these difficult infectious agents, to protect the health of Canadians it is crucial to carry out timely, expert, comprehensive national surveillance on all forms of human and animal TSEs, to investigate promptly, and to act quickly and decisively in a coordinated way among local, provincial and federal jurisdictions as cases arise, and ultimately to eradicate the diseases wherever possible. HGPD is playing an increasingly important role in the national capability for timely detection, aggressive risk management, and advanced research for both conventional and novel forms of TSE (e.g. variant Creutzfeldt-Jakob disease) which pose threats to the health of Canadians. Activities include:

• providing scientific and technical support to the Public Health Agency of Canada's national CJD Surveillance System, including special investigations in connection with particular cases;

• conducting original research on biological mechanisms of TSEs;

• developing new methodologies to detect, monitor and characterize TSEs;

• investigating the unconventional infectious agents of TSEs;

• collaborating with the Canadian Food Inspection Agency on animal TSE initiatives; and

• providing training, education and outreach to professionals and the public.

Through these activities, HGPD plays a critical role in ensuring Canada’s ability to prepare for and respond to actual and potential biological threats posed by TSEs, as demonstrated during the recent BSE situation in Alberta in which HGPD contributed its expertise in molecular genetics, biochemistry and histopathology to the investigation. Another example was the laboratory investigation and confirmation of Canada's first case of vCJD in summer 2002, which allowed Health Canada to collaborate with local and provincial health authorities in a timely manner to minimize secondary exposure of patients to instruments used on the vCJD patient, and to communicate quickly and authoritatively with Canadians on the issue.

A key driver of HGPD's program strategy is the fact that TSEs are fundamentally poorly understood with respect to the molecular nature and adaptive potential of the infectious agent, mechanisms and natural history of disease, and determinants of host susceptibility to infection. As a result, reliable tests to determine the presence of infection, and to differentiate between agent strains in order to trace chains of transmission and follow secular trends in the pathogen population, capabilities that most public-health microbiologists take for granted, for TSEs remain elusive. The knowledge and experience generated from HGPD's research endeavours will be used for example to:

• improve early detection and response in cases or outbreaks of emerging TSEs;

• enhance strategies for "real-time" TSE surveillance, prevention and control;

• understand the nature and magnitude of risks to human health from animal TSEs;

• develop disease risk-management guidelines;

• improve and provide reference support for laboratory technologies to investigate TSEs;

• discriminate among disease variants, including potentially novel forms;

• evaluate host susceptibility and resistance;

• inform regulatory and policy decisions on safety of biologically derived therapeutics; and

• provide scientific background to evaluate candidate TSE therapies.

As a side benefit of its advanced technical approaches to TSEs and its focus on the host term in the infectious disease equation, HGPD has made important pioneering contributions to science and technology capacity at the National Microbiology Laboratory. For example, HGPD has developed microarray technology and other methods of molecular screening to measure host responses to infection at the cellular level. These genomic and proteomic methodologies have immense potential for understanding many diseases, including not only infections as conventionally understood, but also unconventional pathogens such as those of TSEs, and more subtle phenomena such as chronic diseases with infectious risk factors. The program has also

• contributed key elements of bioinformatics infrastructure and expertise to NML,

• works expertly with the genetics of humans,

• and has developed a National Biorepository capable of handling and securely storing human clinical sample collections for research and reference purposes.