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“Asiyah” Yu Lin, Zuoshuang Xiang, Yongqun “Olive” He
University of Michigan Medical School
Ann Arbor, MI 48109, USA
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Classification of Brucella
Bacteria, Proteobacteria, a-Proteobacteria, Rhizobiales, Brucellaceae
Brucella listed as CDC and NIH priority category B pathogen
Species
Host
B. abortus
cattle, human
B. canis
dogs, foxes,
coyotes, human
B. melitensis
sheep, goats,
human
B. neotomae
desert wood rats
B. ovis
rams
B. suis
pigs, human
Gram negative, cocco-bacillus;
facultative intracellular bacterium
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Symptoms of Brucellosis
 Animals:
• Chronic
infection leading to abortion and
infertility
• Clinical signs & symptoms vary with species
- metritis, spondylitis, lameness, paralysis
- testicular swelling, lympadenitis, splenitis
 Humans:
• Clinical
signs & symptoms: fever (Undulant Fever)
anorexia, back pain, fatigue, malaise, myalgia,
sweats, weight loss.
• Mortality rate is low; abortions NOT common
• Clinical manifestations - a lot, including reactive
arthritis (a type of spondylitis)
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Brucellosis Ontology (BO)
An extension of IDO-core
 Uniqueness of BO:

 The first zoonosis disease ontology to be
developed.
 The first Gram-negative bacteria to be
carefully modeled under the scope of IDO.
 The first “select agent” to be modeled.

Goal: data integration and text mining
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Statistics of BO
BO Classes in total : 452
Clinical
Entities
IDO (full)
OGMS
SYMP
FLU
TRANS
VO
Biological
Entities
GO
PRO
CHEBI
NCBI taxonomy
Investigational
Entities
OBI
IAO
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Developing methodology
Top-down & Bottom-up (scenarios)
 Design patterns

 Host-pathogen transmission
 Brucella virulence factors (pathogenesis)
 Intentional release and epidemiology
 Diagnosis and treatment
 Protective antigen
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Host-pathogen interaction/transmission
Entry
Infects
phagocytic
cells
Abortion
Dead fetus, placentas
& secretions
Regional
Lymph
Nodes
Infection
Systemic
Spread
Liver, spleen,
other lymph
nodes; uterus
in ungulates
Unpasteurized milk,
Cheese or dairy products
Transmission to other vertebrates = Zoonosis
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Host-pathogen & transmission modeling
human
brucellosis
human brucellosis
pathogen role
is_realized_by
bearer_of
B.abortus
bearer_of
cattle brucellosis
pathogen role
human
brucellosis
disease course
cattle brucellosis
disease course
has_function
Brucella-infected
is_realized_by Brucella-contaminated
milk producing function
cow
brucellosis patient role
bearer_of
brucellosis patient
Brucella-contaminated
milk drinking process
is_realized_
by
drinking function
human
is_a
is_a
cattle brucellosis
brucellosis
is_a
bearer_of
Brucella-contaminated
milk producing process
is_a
disposition
has_specified_ output
Brucella-contaminated
is_specified milk
_ input_of
is_a
Brucelloa host role
bearer_of
abortion
process
is_realized_by
is_realized_by
is_a
unpasteurized milk
inheres_in
has_part
is_realized_by
bearer_of
cow
Scenario:
A brucellosis patient got
infected by drinking the
unpasteurized Brucellacontaminated milk, which was
produced by a Brucella-infected
cow.
is_realized_by
B. abortus infectious
course
is_a
brucella infectious
course
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Brucella Virulence factors
Brucella virulence factors are aerobic facultative intracellular
pathogen; and it is unusual in:
 It doesn’t have classical virulence factors.
 It maintain an intracellular existence within its host cells, such
as macrophages, dendritic cells, placental trophoblasts,
epithelial cells
 The interactions with those host cells dictate the outcomes of
infection.
Candidate GO terms:
 intracellular viral protein transport (GO:0019060 biological
process)
 establishment of localization in cell (GO:0051649 biological
process)
 entry into host cell (GO:0030260 biological process)
Other terms:
cellular host? …
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Brucella virulence factor modeling
Senario:
Brucella
invading into
macrophages,
the Brucella virb1
is the virulence factor
participant_in
participant_in
Brucella
Process of Brucella’s
replication in macrophages
Process of Brucella’s
survival in macrophages
has_part
establishment of Brucella
intracellular infection
Brucella entry into macrophages
Entry into host cell (GO:0030260)
is_realized_by
Brucella virb1
bearer_of
is_a
Brucella protein
bearer_of
Brucella virulence factor disposition
virulence factor
bearer_of
is_a
is_a
has_part
Brucella protein virulence factor
is_a
is_a
Brucella virulence factor
After reasoning, ‘Brucella virb1’ is_a Brucella protein virulence factor
Statistics: >200 Brucella virulence factors, collected by He Lab, stored in BO already.
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Epidemiology and Intentional release
Brucella can be intentionally released for
bioterrorism
 Scenario:

 Brucella organisms could be released in
aerosol form, by accidental spills of culture
suspensions or live vaccines, or in liquids
such as dairy products or water. Brucellosis
has fairly low fatality rate, but could be used
as an incapacitating agent, as the disease
tends to be chronic, requiring prolonged
treatment
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Brucella intentional release modeling
bioterrorism agent role
bearer_of
Brucella
is_a
is_specified_input_of
aerosolized Brucella
Brucella intentional release
is_specified_output_of
is_specified_input_of
Brucella aerosolization
disinfectant role
bearer_of
bleach (a disinfectant)
has_part
is_a
is_specified_input_of
is_a
planned process
is_a
bleach disinfection of
aerosolized Brucella
is_a
Brucella containment
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Diagnosis of brucellosis
Brucellosis infects many species,
especially cattle, sheep, goats, pigs.
 Different Brucella types infect different
species preferentially.
 Brucellosis presents typically as abortion
in cattle.
 Diagnosis can only be confirmed by
laboratory tests, such as PCR !

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PCR diagnosis based on Brucella OMP-2 Detection
OMP-2 forward primer
has_specified_input
PCR test
has_specified_output PCR product of PCR
has_specified_input for
OMP-2reverse primer
detection
test for detection of
of
Brucella OMP-2
is_specified_input_of Brucella Is_specified_output_of
Brucellacontaminated
OMP-2
body fluids
amplifies
amplifies
part_of
169bp’s region located in
B. abortus
OMP-2 gene
part_of
is_
denoted
_by
is_denoted_by
part_of
B. abortus
genome
part_of
B. abortus
genome
sequence data
OMP-2 reverse primer
sequence data
OMP-2 forward primer
sequence data
part_of
OMP-2 gene
is_denoted_by
B. melitensis
genome
codes_for
OMP-2 protein
hasSize:169
is_denoted
_by
data item
B. meltitensis
genome
sequence data
is_a
letter string
Is_subset_of
(transitive property)
end_with
start_with
Is_subset_of
(transitive property)
is_a
PCR product
sequence
data
is_a
sequence
data
* sequence data
OBI_0000973 14
Continue with PCR diagnosis…
is_a
diagnosis
is_about
Brucellosis diagnosis
clinical manifestation of brucellosis
is_a
inheres_in
data item
???
brucellosis patient
is_a
has_role
laboratory finding of OMP2-detection
has_specified_output
laboratory test
is_a
brucellosis patient role
PCR test for detection
of brucella OMP-2
is_realized_by
brucellosis disease course
is_realized_by
Brucellosis pathogen role
specimen
bearer_of
is_a
contains Brucella-contaminated is_a
Brucella
body fluids
brucellosis patient
derived specimen
is_a
pathogen
part_of
has_part
fever process
patient
is_a
brucellosis
patient
is_a
Homo sapiens
is_a
infected host
is_a
host infected with Brucella
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Protective antigen

Protective antigens are those antigens
that are specifically targeted by the
acquired immune response of the host,
and when introduced into the host body,
are able to stimulate the production of
antibodies and/or cell-mediated
immunity against certain pathogens or
the causes of other diseases.
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Protective antigen modeling
immune response (GO_0006955)
is_a
adaptive immune response
is_a
Brucella protective antigen
stimulated acquired immune response
is_a
Brucella-specific protective T cell
mediated immune response
is_realized_by
antigen role
(OBI_1110034)
is_a
Brucella protective antigen role
bearer_of
MaterialEntity(OBI)
antigen
is_a (OBI_1110034)
is_a
Brucella protective antigen
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Treatment


A scenario from WHO recommend treatment is
as following :
Treatment of uncomplicated cases in adults
and children eight years of age and older:
doxycycline 100 mg twice a day for six weeks
+ streptomycin 1 g daily for two to three weeks.
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Treatment Modeling
brucellosis treatment
objective
is_a
objective specification
has_part
Is_concritization_of (WHO standard
treatment specification for human
brucellosis)
realizes
Doxycycline specification in
WHO standard treatment for
human brucellosis
WHO standard doxycycline
treatment for human brucellosis
patient role
is_a
age
is_specified_input_of
has_role
inheres_in
brucellosis
patient
100 mg twice a
day for six weeks
is_concretized_as
is_realized_by
quality
plan
specification
part_of
WHO standard treatment
for human brucellosis
>=8
is_a
doxycycline
is_a
human
* Green box shows the difficulties
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A proposal modeling for age
Specifically, adults and children eight years of age and older
8 year
has_quality specified
quality
is_a
age
inheres_in
brucellosis patient eight years of
age and older
has_function
viable function
* Black and blue arrows differ two
kinds of modeling
is_realized_by
living process
has_temporal_region
connected temporal region
of living till now
start_with
starting temporal
boundary
is_a
is_a
the 8th
year
temporal boundary
end_with
ending temporal
boundary
is_a
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Open for discussion
Interactions between upper and lower ontologies



When upper ontology changes…
Downstream ontologies should provide new terms to
upper ontologies
The granularity for modeling


For example, shall we model the molecular level of
virulence factor?
Symptoms and signs:


The established vocabulary is not sufficient, neither
OGMS nor Symptom Ontology
How to model: (IAO’s scope)


100 mg twice a day for six weeks
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Acknowledgments
OBI and IDO developers
Funding: NIH-NIAID R01AI081062
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