Pathogen gene info - Centre for Microbial Diseases and Immunity ...

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Feb 20, 2013 (4 years and 5 months ago)

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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

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?

Prioritize for further biological study.


-

Previously studied biologically?

-

Can UBC microbiologists study it?


-

C. elegans

homolog?


Evolutionary significance.


-

Horizontal transfer? Date of transfer?
Coevolution? Similar by chance?

Modify
screening
method
/algorithm

Approach

Database: pathogen gene info (+ similar host/model host gene info)

Prioritized candidates


If
C. elegans
homolog

-

Target gene for
knockout.

-

Analysis of knockout
(expression chip,
pathogen infection)

-

GFP fusion analysis


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)

C. elegans

gene info
continually exchanged
with microbiologists

Pathogen gene info

continually exchanged
with eukaryotic geneticists

Approach

Informatics/Bioinformatics


Genome Sequence Centre, BC


Centre for Molecular
Medicine and Therapeutics


Evolutionary Theory


Dept of Zoology


Dept of Botany


Canadian Institute for
Advanced Research

Pathogen Functions


Dept. Microbiology


Biotechnology Laboratory


Dept. Medicine


BC Centre for Disease Control

Host Functions


Dept. Medical Genetics


C. elegans Reverse Genetics
Facility


Dept. Biological Sciences SFU


Interdisciplinary group


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

Power of the Approach

Eukaryotic
-
like pathogen genes

-

YopH, a protein
-
tyrosine phosphatase, of
Yersinia pestis


-

Enoyl
-
acyl carrier
protein reductase
(involved in lipid
metabolism) of
Chlamydia trachomatis

0.1

Aquifex aeolicus

Haemophilus influenza

Escherichia coli

Anabaena

Synechocystis

Chlamydia trachomatis

Petunia x hybrida

Nicotiana tabacum

Brassica napus

Arabidopsis thaliana

Oryza sativa

100

100

100

96

63

64

52

83

99

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.



Fundamental
research


Interdisciplinary


Major potential
impact


Lack of fit with
alternative funding
sources

Peter Wall Major Thematic Grant

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