Goals of PATHOGENOMICS

related researchChief Scientist Office

Ministry of Health

Israel

BOTTOM-UP

Potential future research topics

Enteropathogenes

• E. coli – enteropathogenic, enterohemorrhagic O157

• Structure and function of the EPEC/EHEC Type III protein system

• Delivery of toxic effector proteins into infected mammal – the type III secretion system

I. Rosenshine

• Genomic and bioinformatic screens for identification of genes in EPEC and EHEC, including genes encoding for toxic proteins

• Genomic global regulation ( transcriptom) of expression of genetic network encoding for virulence

• Formation and function of surface structures including type III secretion system

I.Rosenshine

Salmonellosis

The most important and frequently occuring foodborne disease worldwide

However

S. Yaron

Genetic background

Leads to variety of symptoms caused by the pathogenic Salmonella serovars, from

Typhoid fever-like infections

To

Focal enteritis

S. Yaron

Effector proteins translocated directly to the target cells

Questions

S. Yaron

Genetic background

What are the polymorph of the sequence and

regulation of expression of the effector

proteins among the salmonella serovars?

S. Yaron

Genetic background

Is there any Correlation between potency of

S. Enterica strains and expression profile

of the virulence factors?

S. Yaron

Genetic background

What is the cell biological function of

each protein in the network of the virulence

associated effector proteins?

S. Yaron

How do they contribute to qualify a strain either towards typhoid fever-like infections, focal enteritis, or an epidemic spread?

S. Yaron

In addition

Molecular basis for development of antibiotic resistance– Screening for presence of antibiotic resistance

genes or mutations among resistant isolates– Development of micro- array and real-time PCR-

based diagnostic capabilities for detection of antibiotic resistance genes and/or mutations conferring antibiotic resistance

S. Yaron

Group A Streptococcus (GAS)

• Life threatening highly invasive disease such as toxic shock syndrome (TSS) and necrotizing fasciitis (NF)

• Last two decades – marked increase in incidence worldwide

• High mortality rates: 20-60%• Develops resistance to macrolides and

erythromycin

E. Hanski

In the present…

• Better understanding why certain serotypes of GAS are associated with specific diseases

• It appears that the profile of expressed virulence factors is what determines the severity of the disease

E. Hanski

Interaction between Bacteria and Hosts defense mechanism

• Profile of expressed genes in the presence and absence of the competence stimulating peptide SilCR which attenuates the virulence– In vitro– In vivo (murine model)

E. Hanski

Legionella pneumophilapathogenesis system

• Type – IV secretion complex composed from 25 Icm/Dot proteins

G. Segal

• Effector proteins – probably more than 30, that translocate into host cells via this secretion system

• Uncovering the function of these components, by using the genomic sequences available for 3 L. pneumophila strains, is one of our major research goals

Legionella pneumophilapathogenesis system

G. Segal

Bacillus anthracis

• Selection of novel vaccine candidates and novel virulence factors– proteins are assayed by classical or high

throughput functional In- silico identified putative in-vitro and in-vivo screening and evaluation methods

A. Shafferman

Yersinia pestis

• Identification of genes involved in its pathogenesis by applying a combination of random signature tagged mutagenesis technique (STM) with genomic analyses

A. Shafferman

Listeria• Microbial Thiol-

Disulfide Redox Metabolism

• Genetic and Biochemical studies of Ribonucleotide Reductase ( coenzyme B12 cross regulates expression of class Ia and II ribonucleotide reductases via riboswitch and cofactor functions)

Y. Aharonowitz,

G. Cohen

• Novel route for synthesis of gutathione in bacterial pathogenes: A multifunctional fused protein (GshF) integrates the two catalytic activities

• Development of new selective and essential targets for antibiotics, and their use in specific drug discovery

programs

Y. Aharonowitz,

G. Cohen

Listeria

Aspergillus

• Important opportunistic group of pathogens in immunocompromised patients

• Fungus can spread from initial site of infection to lungs and internal organs

Invasive Aspergillosis Often fatal

N. Osherov

• High mortality : more than 90% if left untreated and 50-70% after aggressive treatment

N. Osherov

Research projects and goals

• Conidial (spore) germination and adhesion• Bioinformatic approach to identify and

characterize novel Aspergillus cell-wall proteins• The response evoked in the host lung cells

during infection• Aspergillus resistance to antifungal drugs and

novel drug combinations

N. Osherov