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WP6.2 Genomics and microbiology. Overall Objective: To demonstrate how the integration of pathway biology And host/ pathogen genomics can contribute to clinical diagnosis and treatment of infected patients. 1 st Annual Technical Review, Brussels, 16 th March 2005. UEDIN. LEIC. INFORMA.

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WP6.2 Genomics and microbiology

Overall Objective:

To demonstrate how the integration of pathway biology

And host/ pathogen genomics can contribute to clinical

diagnosis and treatment of infected patients

1st Annual Technical Review, Brussels, 16th March 2005


UEDIN

LEIC

INFORMA

IMIM

FORTH

WP6.2 Genomics and microbiology

Work Package approach

To forge a collaboration between partners through

the integrated study of host/ pathogen interactions

WP6.2 Partners

Project Lead:

P Ghazal

K Robertson

M Mewissen

G Sing

A Livingston

T Brooks

M Alba

B Oliva

Joan Planas

Roberto Ricci

Maurizio Zazzi

M Reczko

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

Host pathway: Interferon Signalling

> A family of related proteins

> Bind to specific receptors

Activation of Interferon signalling pathways results in a defined gene expression and:

Increased

antigen presentation

Inhibition of

cellular proliferation

Development of an

inflammatory response

An anti-infective state

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

Interferon is a key Inflammatory mediator

with a number of notable therapeutic applications

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

Medical Informatics

Bioinformatics

Viral Immuno-

modulatory

Interactions

Clinical

Host/ Viral

Interactions

Outcomes:

Secretome

1. Further insight into the virus-host interaction

2. Identification of biomarkers for validation

and potential therapeutic exploitation

3. Methods for storage, manipulationand

exchange of phenotype data

Protein Interaction Network

microRNA

Phenotype DB

Microarray/

Proteomic

Profiling

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

Viral Immunomodulatory Interactions (IMIM/ UEDIN)

Objectives:

To characterise protein-protein interactions:

1. Within host interferon signalling pathway

2. Between virus and host proteins

Objective 1. Application of PIANA to identification of virus/ host protein interaction

PIANA

Yeast interactions experimentally

defined by yeast 2 hybrid approach

Gene

COG code

x

1

2

3

x

y

z

x

7 predicted CMV-Human

protein interactions

e.g. KPNA4

x

x

2. Interacting pairs in yeast defined

which have at least 1 COG code in

common with CMV proteins

1. COG codes assigned

to Human CMV proteins

3. Orthologous human

partner identified

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

Viral Immunomodulatory Interactions (IMIM/ UEDIN)

KPNA4 (importin alpha 3)

Functions in import of IRF3

into nucleus from cytoplasm

Kumar KP, McBride KM, Weaver BK, Dingwall C,

Reich NC.Regulated nuclear-cytoplasmic

localization of interferon regulatory factor 3, a

subunit of double-stranded RNA-activated factor 1

Mol Cell Biol 2000 Jun 1;20(11):4159-68.

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

Sub-cellular Logic Interaction map of interferon signalling pathway submodule

CMV dUTPase

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

How can a bioinformatics analysis of host-pathogen pathway interactions facilitate clinical patient management?

Anti-Retroviral Cohort Analysis (ARCA) db

> Stores clinical and HIV genome data (>3000 patients) from multicentric observational cohort in Italy

> Enables exploitation of HIV genotype data to advanced HAART therapy

230 patients identified

Multiple samples available

Full treatment history

HIV genotypic data available

Key Question: Can host bioinformatics pathway information be incorporated

into medical informatics DB and predictive models?

100 patients

Host

Pathogen

HLA typing

IFN genotyping

CMV status

Hepatitis G status

Curation into ARCA DB

Therapeutic modelling

Clinical Host/ Pathogen

Interaction data

IFN Knowledgebase

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

Milestones and Objectives

Year 2

Year 3

Year 1

Project definition

(UEDIN, IMIM, LEIC, FORTH, INFORMA)

Data acquisition and curation

Protein to protein interactions defined

miRNA stem loop identification

Novel genes experimentally identified

Genotyping/ infection status

Data analysis &

Integration

Pathway Biomarker Validation

POC study on benefit from integrating clinical and bio- informatics

Biomarker definition

Project Plan

Preparation of

Publications

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

Efforts towards characterisation of IFN signalling pathway and identification of potential/ novel genes/ proteins of (clinical) interest

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

Objective 1:

Identification of a core set of interferon Gamma-related genes/ proteins around which initial studies of WP6.2 will focus

UEDIN

‘novel’

Genes

(300 – 400)

263 Core interferon gamma response genes identified

Human/Mouse,

Variety of cell types

Literature Review

Ingenuity

Pathway Assist

Core

Literature

‘novel’

genes

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

Literature Review (PubMed)

Several Hundred gene/ gene products

Subjective/ Objective Reduction and assortment

Antigen Presentation

Jak/ STAT

IRF(s)

Apoptosis

Ingenuity

Pathway Assist

Further novel signalling interactions identified

Core genes for analysis

Annotation (inc hand-curated protein-protein interaction data)

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

Actual number of genes involved in interferon response likely to be >1000

A system is required for storage and application of data

‘Interferon Knowledgebase’

1st Annual Technical Review, Brussels, 16th March 2005


WP6.2 Genomics and microbiology

  • Year 1 aims for knowledgebase development:

  • 1) Web accessible repository of interferon signalling-related information

  • 2) Incorporate data generated in course of InfoBiomed project

  • Year 2 aims for knowledgebase environment

  • Incorporate further signalling pathway information (type 1 interferon, TLR

  • TNF-alpha) selected via objective criteria.

  • 2) To integrate database with GPX database and allow

  • rapid focussed analyses of microarray/ proteomic data

  • 3) Output signalling pathway information from database in XML

  • (SBML-like) allowing modelling/ simulation

1st Annual Technical Review, Brussels, 16th March 2005


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