He Lab Overview:Systems Biology Studies of Host-pathogen

Interactions and Vaccines

(Workshop on Data, Text, Web & Social Network Mining)

Yongqun “Oliver” He

Unit for Laboratory Animal MedicineDepartment of Microbiology and Immunology

Center for Computational Medicine and BioinformaticsUniversity of Michigan Medical School

Ann Arbor, MI 48109

Overview

Brucella and Brucellosis

• Brucella: intracellular bacterium that causes most common zoonotic brucellosis in humans and animal

• Lab focuses: Brucella pathogenesis & vaccine • Lab goal: Develop a human Brucella vaccine.

Brucella vaccine-infected macrophages from wild type mice

Brucella vaccine-infected macrophages from Caspase-2knockout mice

Light microscopy

Annexin V-PI fluorescence

Caspase-2 mediated cell death of macrophages induced by Brucella vaccines but not by virulent Brucella strains

miniTUBA: dynamic Bayesian network (BN) analysis system

-- http://www.minituba.org/

Experimentally Confirmed:Casp2, Tnf, Nf-kb, Casp1

Predicted network of Brucella-induced macrophage cell death

miniTUBA: A pipeline – - data input, - missing data prediction, - dynamic BN calculation, - prediction of future event,- output visualization

Brucella_wboA_mutation

Nfkbia

Nfkb2 Tnf

Casp2

Il1b

Macrophage_death

Casp1

Casp7

Irak2

BN+1: Bayesian network expansion-- Iteratively test all possible genes

Confirmed

BN+1 identified new ROS and biofilm regulators (PMID: …)

BN+1: find pathway hidden factors

Limix: Literature mining & curation system-- http://www.limix.org

• Limix allows us to manually curate a large amount of high quality data in a short period of time.

• Support: literature search; data input, edition and submisison; data review before publication; versioning

PHIDIAS: Pathogen-Host Interaction Data Integration and Analysis System

-- http://www.phidias.us/

• Focus: PHI – Pathogen-host interaction• Statistics: ~60 pathogens, >700 genomes• Model organism: Brucella

VIOLIN: Vaccine Investigation and Online Information Network

-- http://www.violinet.org

• Overall goal: A vaccine research database & vaccine data analysis system

• Manually curated 454 vaccines from 73 pathogens

• Many programs, e.g., Vaxign (Vaccine Design) and VO (Vaccine Ontology)

VIOLIN web cover page

Vaxign: Vaccine Design--the 1st web-based vaccine design system

based on reverse vaccinologyhttp://www.violinet.org/vaxign

• Reverse vaccinology: predict vaccine targets first from bioinformatics analysis of genomes

• Applications: UPEC, Brucella, Francisella, …

Input(PHP/HTML)

Subcellular Localization

Transmembrance Domains

Adhesin Probability

Similarity to Host Proteins

MHC-Epitope Binding

Sequence Exclusion

ResultsWeb Browser

Output(PHP/HTML)

Query

MySQL Database

PHP/SQL

Dynamic Computation

Process(PHP/SQL)

Retrieve

Filter

FunctionalAnalysis(DAVID)

or: Query

Sequence Conservation

TransmembranceTopology

(α-helix, b- barrel)

VO: Vaccine Ontology-- a community effort

• Vaccine Ontology (VO): Controlled vocabulary of terms Vaccine Ontology (VO): Controlled vocabulary of terms and relations (“ontology”) in the vaccine domainand relations (“ontology”) in the vaccine domain

• Allow computers to understand and analyze dataAllow computers to understand and analyze data• Support computer-assisted reasoningSupport computer-assisted reasoning

http://www.violinet.org/vaccineontology

VO-based literature mining

• VO-based SciMiner: to index vaccine literature based on VO terms. o Joint work with Junguk Hur, Eva Feldman

• VO-based literature discover of IFNG interaction networkso Joint work with Arzucan Özgür, Dragomir R.

Radev

Acknowledgements

Funding: NIH-NIAID, GLRCE, NCIBIUniversity of Michigan

He Laboratory / U of Michigan (UM) UM Collaborators:• Peter Woolf• Brian Athey• Harry Mobley• Arzucan Özgür, Dragomir R. Radev• Junguk Hur, Eva Feldman• Dongjuan Dai, Chuanwu Xi

* Dr. Fang Chen** Andrew Hodges *** Zuoshuang “Allen” Xiang

Not in picture:-- Sirarat Sarntivijai-- Keerthi S. Sannareddy

**** **

Vaccine Ontology Collaborators:• Barry Smith (Buffalo)• Lindsay Cowell (Duke)• Bjoern Peters (La Jolla Institute)• Alan Ruttenberg (Sci. Commons)• Ryan Brinkman (BC, Canada)• Melanie Courtot (BC, Canada)• …