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“Asiyah” Yu Lin, Zuoshuang Xiang, Yongqun “Olive” HeUniversity of Michigan Medical School

Ann Arbor, MI 48109, USA

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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

Bacteria, Proteobacteria, a-Proteobacteria, Rhizobiales, Brucellaceae

Gram negative, cocco-bacillus;facultative intracellular bacterium

Brucella listed as CDC and NIH priority category B pathogen

Classification of Brucella

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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)

Symptoms of Brucellosis

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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

Clinical Clinical EntitiesEntities

Biological Biological EntitiesEntities

Investigational Investigational EntitiesEntities

IDO (full)

OGMS

SYMP

FLU

TRANS

VO

GO

PRO

CHEBI

NCBI taxonomy

OBI

IAO

BO Classes in total : 452

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Developing methodology

Top-down & Bottom-up (scenarios) Design patterns

Host-pathogen transmissionBrucella virulence factors (pathogenesis)Intentional release and epidemiologyDiagnosis and treatmentProtective antigen

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Host-pathogen interaction/transmission

Entry RegionalLymphNodes

Infects

phagocyticcells

SystemicSpread

InfectionAbortion

Unpasteurized milk, Cheese or dairy products

Transmission to other vertebrates = Zoonosis

Liver, spleen, other lymphnodes; uterus in ungulates

Dead fetus, placentas& secretions

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B.abortus

cattle brucellosis pathogen role

bearer_of

cattle brucellosis disease course

is_realized_by

cattle brucellosis

is_realized_by

brucellosis patient role cattle brucellosis

is_realized_by

brucellosis

is_a

Brucella-infected cow

Brucella-contaminated milk producing function

has_function

bearer_of

abortionprocess

has_part

brucella infectiouscourse

B. abortus infectiouscourse

is_a

human Brucelloa host role

bearer_of is_realized_by

cowbearer_of

Brucella-contaminated milk

is_ais_a

Brucella-contaminatedmilk 　 producing process

Brucella-contaminatedmilk drinking process

has_specified_ output

is_specified_ input_of

is_realized_by

drinking function

inheres_in

disposition

is_a

is_realized_by

brucellosis patient

bearer_of

human brucellosis

human brucellosis disease course

is_realized_by

Host-pathogen & transmission modeling

is_a

human brucellosispathogen role

bearer_of

drinking function

cow

Scenario: A brucellosis patient got infected by drinking the unpasteurized Brucella-contaminated milk, which was produced by a Brucella-infected cow.

unpasteurized milk

is_a

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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

Brucella protein virulence factor

bearer_of

Brucella virulence factor disposition

is_realized_by

Brucella virulence factoris_a

virulence factor

is_a

Brucella virb1

Brucella protein

is_a

Statistics: >200 Brucella virulence　factors,　collected　by　He　Lab,　stored in BO already.

bearer_of

establishment of Brucella intracellular infection

Process of Brucella’s survival in macrophages

has_part

Brucella entry into macrophages

Brucella

has_part

Process of Brucella’s replication in macrophages

Entry into host cell (GO:0030260)

is_a

is_a

After reasoning, ‘Brucella virb1’ is_a Brucella protein virulence factor

Senario: Brucellainvading intomacrophages, the Brucella virb1 is the virulence factor

bearer_of

participant_in participant_in

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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

planned process

is_a

Brucella aerosolization

aerosolized BrucellaBrucella

is_specified_input_ofis_a

Brucella containment

bleach disinfection of aerosolized Brucella

is_a

disinfectant role

is_specified_input_of

bleach (a disinfectant)

bearer_of

is_a

Brucella intentional release modeling

is_specified_output_of

bioterrorism agent role

bearer_of

has_part

is_specified_input_ofis_a

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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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OMP-2 forward primer

OMP-2reverse primer

Brucella-contaminatedbody fluids

is_specified_input_of

PCR test for detection of Brucella OMP-2

has_specified_input

has_specified_outputhas_specified_input

Is_specified_output_of

PCR product of PCR test for detection of Brucella OMP-2 hasSize:169

OMP-2 forward primer sequence data

OMP-2 reverse primer sequence data

is_denoted_by

is_denoted_by

PCR product sequence data Is_subset_of

(transitive property)

Is_subset_of (transitive property)

B. abortus genome sequence data

169bp’s region located in OMP-2 gene

amplifies

OMP-2 geneB. abortus genome

B. melitensis genome

B. meltitensis genome sequence data

start_with

end_with

part_ofpart_ofpart_ofis_

denoted_by

is_denoted_by

OMP-2 protein

codes_for

B. abortus

part_of

part_of

PCR diagnosis based on Brucella OMP-2 Detection

* sequence dataOBI_0000973

codes_for

amplifies

sequence data

letter string

data item

is_a

is_a

is_a

letter string

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Continue with PCR diagnosis…

Brucella Brucella-contaminatedbody fluids

contains brucellosis patient derived specimen

is_a brucellosis patient

part_ofHomo sapiens

is_a

host infected with Brucella

is_a

Brucellosis diagnosis clinical manifestation of brucellosis

brucellosis disease course fever process

laboratory test

has_specified_output

is_about

has_part

infected hostis_a

Brucellosis pathogen role

is_a

specimen

is_apatient

is_a

pathogen

bearer_of

has_role

PCR test for detectionof brucella OMP-2

is_a

diagnosisis_a

data item

is_a

brucellosis patient

inheres_in

is_realized_by

brucellosis patient role

is_realized_by

laboratory finding of OMP2-detectionis_a

???

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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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Brucella protective antigen

bearer_of

Brucella protective antigen role

is_realized_by

antigen(OBI_1110034)

is_a

is_aMaterialEntity(OBI)

Brucella protective antigen stimulated acquired immune response

is_aantigen role(OBI_1110034)

immune response (GO_0006955)

is_a

Brucella-specific protective T cell mediated immune response

adaptive immune response

is_a

Protective antigen modeling

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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Is_concritization_of (WHO standard treatment specification for human brucellosis)

objective specification

brucellosis patient

human

is_a plan specification

brucellosis treatment objective

has_part

is_a

WHO standard treatment for human brucellosis

realizes

patient role

has_role

is_aage

part_of

Doxycycline specification in WHO standard treatment for human brucellosis

is_specified_input_of

100 mg twice a day for six weeks

doxycycline>=8

inheres_inquality

WHO standard doxycycline treatment for human brucellosis

is_concretized_as

* Green box shows the difficulties

Treatment Modeling

is_realized_by

is_a

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A proposal modeling for age

brucellosis patient eight years of age and older

ageinheres_in

quality

living process

viable function

has_function

is_realized_by

connected temporal region of living till now

has_temporal_region

starting temporal boundary ending temporal

boundary

start_with end_with

8 year

has_quality specifiedis_a

the 8th year

Specifically, adults and children eight years of age and older

is_a

* Black and blue arrows differ two kinds of modeling

temporal boundaryis_a 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