Goals of PATHOGENOMICS related research Chief Scientist Office Ministry of Health Israel

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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 pneumophila pathogenesis 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 pneumophila pathogenesis 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 % 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