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Pathogenomics
Goal:
Identify previously unrecognized
mechanisms of microbial
pathogenicity using a unique
combination of informatics,
evolutionary biology, microbiology
and genetics.
Pathogenicity
Processes of microbial pathogenicity at the molecular
level are still minimally understood
Pathogen proteins identified that manipulate host
cells by interacting with, or mimicking, host proteins.
Idea: Could we identify novel virulence
factors by identifying pathogen genes
more similar to host genes than you
would expect based on phylogeny?
Pathogens
Anthrax
Paratyphoid/enteric fever
Cat scratch disease
Peptic ulcers and gastritis
Chlamydia
Periodontal disease
Cholera
Plague
Dental caries
Pneumonia
Diarrhea (E. coli etc.)
Salmonellosis
Diphtheria
Scarlet fever
Epidemic typhus
Shigellosis (bacillary dysentery)
Mediterranean fever
Sleeping sickness
Gastroenteritis
Strep throat
Giardia
Syphilis
Gonorrhea
Toxic shock syndrome
Legionnaires' disease
Tuberculosis
Leishmaniasis
Tularemia
Leprosy
Typhoid fever
Leptospirosis
Urethritis
Listeriosis
Urinary Tract Infections
Lyme disease
Whooping cough
Malaria
Meningitis
Necrotizing fasciitis
Yeast infection
Some hospital-acquired infections, animal/plant infections
Approach
Screen for candidate genes.
Search pathogen genes against sequence
databases. Identify those with notable
similarity to eukaryotic genes.
Rank candidates.
- how much like host protein?
- info available about protein?
Evolutionary significance.
- Horizontal transfer? Date of transfer?
Coevolution? Similar by chance?
Prioritize for further biological study.
- Previously studied biologically?
- Can UBC microbiologists study it?
- C. elegans homolog?
Modify
screening
method
/algorithm
Approach
Prioritized candidates
If C. elegans homolog
- Target gene for
knockout.
- Analysis of knockout
(expression chip,
pathogen infection)
- GFP fusion analysis
C. elegans gene info
continually exchanged
with microbiologists
If pathogen studied by
UBC microbiologists
- Obtain knockout
- Analysis of knockout
(expression chip,
pathogenicity in C. elegans
or other model
- Subcellular localization
If pathogen is not a
focus of UBC group
Contact other groups
(possible
collaboration)
Pathogen gene info continually exchanged
with eukaryotic geneticists
Database: pathogen gene info (+ similar host/model host gene info)
Interdisciplinary group
Informatics/Bioinformatics
Evolutionary Theory
• Genome Sequence Centre, BC
• Centre for Molecular
Medicine and Therapeutics
• Dept of Zoology
• Dept of Botany
• Canadian Institute for
Advanced Research
Pathogen Functions
Host Functions
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• Dept. Medical Genetics
• C. elegans Reverse Genetics
Facility
• Dept. Biological Sciences SFU
Dept. Microbiology
Biotechnology Laboratory
Dept. Medicine
BC Centre for Disease Control
Power of the Approach
• Interdisciplinary team
unique ideas and collaborations
• Expression-independent method
• Automated approach
continually updated
• Better understanding: pathogen gene and similar host gene
• Insight into horizontal gene transfer events and the
evolution of pathogen-host interactions.
• Public database
– other researchers may capitalize on
the findings
– promote further collaboration
Eukaryotic-like pathogen genes
Aquifex aeolicus
96
Haemophilus influenza
100
Escherichia coli
Anabaena
- YopH, a proteintyrosine phosphatase, of
Yersinia pestis
100
Synechocystis
100
63
Chlamydia trachomatis
64 Petunia x hybrida
83
0.1
Nicotiana tabacum
Brassica napus
99
Arabidopsis thaliana
52
Oryza sativa
- Enoyl-acyl carrier
protein reductase
(involved in lipid
metabolism) of
Chlamydia trachomatis
Database front
end for
Pathogens
Candidate
proteins
are ranked
Customized
blast result
shows
pair-wise
distance and
species
information
Customize the
tree-building
parameters
View the
constructed tree.
Organism
information
is shown
Also see
prokaryotic-like
proteins within
Eukaryotic
genomes
Important if
transfer is
between a
prokaryote
and an
eukaryotic
parasite
Bacterium Eukaryote Horizontal Transfer
Trichomonas vaginalis Sialidase
is 92-95% similar to Sialidase of
Pasteurellaceae bacteria.
Sialidase is a virulence factor
used by some bacteria to
parasitize the mucous membranes
of animals.
Peter Wall Major Thematic Grant
• Fundamental
research
• Interdisciplinary
• Major potential
impact
• Lack of fit with
alternative funding
sources
Acknowledgements
• Pathogenomics group
– Ann M. Rose, Steven J. Jones, Yossef
Av-Gay, David L. Baillie, Fiona S. L.
Brinkman, Robert Brunham, Stefanie
Butland, Rachel C. Fernandez, B. Brett
Finlay, Robert E.W. Hancock, Christy
Haywood-Farmer, Hans Greberg,
Patrick Keeling, Audrey de Koning,
Don G. Moerman, Sarah P. Otto, B.
Francis Ouellette, Iain E. P. Taylor,
Ivan Wan.
• Peter Wall Foundation