Toward a Brucellosis ontology

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Toward a Brucellosis ontology

• 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 Biological Entities Investigational Entities
IDO (full) OGMS SYMP FLU TRANS VO GO PRO CHEBI NCBI taxonomy 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
Infects
Regional
Systemic
Entry
Lymph
Spread
Nodes
phagocytic cells
Liver, spleen, other lymph nodes uterus in
ungulates
Infection
Abortion
Unpasteurized milk, Cheese or dairy products
Dead fetus, placentas secretions
Transmission to other vertebrates Zoonosis
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Host-pathogen transmission modeling
human brucellosispathogen role
bearer_of
B.abortus
human brucellosis
bearer_of
has_part
is_realized_by
is_realized_by
cattle brucellosis pathogen role
cattle brucellosis disease course
abortionprocess
human brucellosis disease course
is_realized_by
has_function
Brucella-infected cow
Brucella-contaminated milk producing function
is_realized_by
is_a
cattle brucellosis
cattle brucellosis
brucellosis
brucellosis patient role
is_a
is_a
is_realized_by
bearer_of
bearer_of
disposition
brucellosis patient
Brucella-contaminatedmilk producing process
has_specified_ output
Brucella-contaminatedmilk drinking process
Scenario A brucellosis patient got infected by
drinking the unpasteurized Brucella-contaminated
milk, which was produced by a Brucella-infected
cow.
Brucella-contaminated milk
is_realized_by
is_a
is_specified _ input_of
is_a
drinking function
drinking function
unpasteurized milk
inheres_in
human
Brucelloa host role
cow
cow
bearer_of
is_realized_by
bearer_of
brucella infectiouscourse
B. abortus infectiouscourse
is_a
is_a
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Brucella Virulence factors

• Brucella virulence factors are aerobic
  facultative intracellular pathogen and it is
  unusual in
• It doesnt 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
  (GO0019060 biological process)
• establishment of localization in cell (GO0051649
  biological process)
• entry into host cell (GO0030260 biological
  process)
• Other terms
• cellular host?

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Brucella virulence factor modeling
Senario Brucella invading intomacrophages,
the Brucella virb1 is the virulence factor
participant_in
participant_in
Brucella
Process of Brucellas survival in macrophages
Process of Brucellas replication in
macrophages
has_part
Brucella entry into macrophages
establishment of Brucella intracellular infection
is_a
has_part
Entry into host cell (GO0030260)
is_realized_by
bearer_of
bearer_of
Brucella virulence factor disposition
Brucella virb1
virulence factor
is_a
bearer_of
is_a
is_a
is_a
Brucella protein virulence factor
Brucella virulence factor
Brucella protein
After reasoning, Brucella virb1 is_a Brucella
protein virulence factor
Statistics gt200 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
disinfectant role
bearer_of
is_specified_input_of
is_a
bearer_of
aerosolized Brucella
Brucella intentional release
Brucella
bleach (a disinfectant)
is_specified_output_of
is_specified_input_of
has_part
is_a
is_specified_input_of
is_a
bleach disinfection of aerosolized Brucella
is_a
planned process
Brucella aerosolization
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
has_specified_input
OMP-2 forward primer
PCR test for detection of Brucella OMP-2
has_specified_output
PCR product of PCR test for detection of Brucella
OMP-2
has_specified_input
OMP-2reverse primer
hasSize169
Is_specified_output_of
is_specified_input_of
Brucella-contaminated body fluids
amplifies
amplifies
part_of
169bps region located in OMP-2 gene
B. abortus
is_denoted_by
part_of
part_of
is_ denoted_by
B. abortus genome
part_of
part_of
B. melitensis genome
OMP-2 gene
is_denoted_by
is_denoted_by
codes_for
codes_for
data item
B. abortus genome sequence data
B. meltitensis genome sequence data
OMP-2 protein
is_a
letter string
letter string
Is_subset_of (transitive property)
is_a
OMP-2 reverse primer sequence data
end_with
PCR product sequence data
is_a
sequence data
Is_subset_of (transitive property)
OMP-2 forward primer sequence data
start_with
sequence data OBI_0000973
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Continue with PCR diagnosis
is_about
is_a
Brucellosis diagnosis
clinical manifestation of brucellosis
diagnosis
is_a
inheres_in
data item
???
brucellosis patient
is_a
has_role
laboratory finding of OMP2-detection
has_specified_output
brucellosis patient role
is_a
PCR test for detection of brucella OMP-2
laboratory test
is_realized_by
has_part
brucellosis disease course
fever process
is_realized_by
Brucellosis pathogen role
specimen
patient
is_a
is_a
bearer_of
part_of
contains
Brucella-contaminated body fluids
brucellosis patient derived specimen
is_a
brucellosis patient
is_a
Homo sapiens
Brucella
is_a
is_a
is_a
pathogen
host infected with Brucella
infected host
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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
is_a
Brucella protective antigen stimulated acquired
immune response
Brucella-specific protective T cell mediated
immune response
is_realized_by
is_a
antigen role(OBI_1110034)
Brucella protective antigen role
bearer_of
is_a
antigen(OBI_1110034)
Brucella protective antigen
MaterialEntity(OBI)
is_a
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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
is_a
brucellosis treatment objective
objective specification
has_part
Is_concritization_of (WHO standard treatment
specification for human brucellosis)
is_a
plan specification

realizes
part_of
Doxycycline specification in WHO standard
treatment for human brucellosis
100 mg twice a day for six weeks
WHO standard treatment for human brucellosis
is_concretized_as
WHO standard doxycycline treatment for human
brucellosis
is_realized_by
patient role
is_specified_input_of
gt8
has_role
doxycycline
inheres_in
is_a
is_a
brucellosis patient
human
age
quality
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
is_a
inheres_in
brucellosis patient eight years of age and older
age
quality
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
end_with
starting temporal boundary
the 8th year
ending temporal boundary
is_a
is_a
is_a
temporal boundary
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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 (IAOs scope)
• 100 mg twice a day for six weeks

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Acknowledgments
OBI and IDO developers Funding NIH-NIAID
R01AI081062