Schistosomiasis: Exploring Genomic Information for Control

Stephen Gikuru

Egerton University-Kenya

Irish Forum for Global Health Conference 30th Nov 2010, NUIM

A public health problem

Neglected parasitic disease that ranks 2nd to malaria in morbidity.

Despite 50 years of concerted control efforts.

Over 210 million people in 76 countries still infected worldwide.

80% of affected population from Sub- Saharan Africa.

Poverty related diseasePrevalent in tropical and sub-tropical areas.

Affects poor communities lacking potable water and adequate sanitation.

Children and at higher risk in endemic areas due to play habits.

Occupational hazard

Affects women doing domestic chores in infested water - washing clothes.

Also people in occupations in contact with infested water such as fishermen, farmers and irrigation workers.

Schistosomiasis parasitesCaused by blood flukes of the genus Schistosoma (phylum Platyhelminthes).

3 major human species S. mansoni hepatic & intestinal

schistosomiasis S. japonicum

S. hematobium urinary schistosomiasis

S. mansoni- Hepatic/intestinal Schistosomiasis- Africa, Middle East, Caribbean, Brazil, Venuzuela, SurinameS. Japonicum – Hepatic/intestinal Schistosomiasis- China, Indonesia, Philippines.S. haematobium- Urinary Schistosomiasis- Africa, Middle East

Global epidemiology of schistosomiasis (Adapted from CDC)

Life Cycle of SchistosomeAdapted fromCDC

Life cyle is Complex – Involves intermediate Snail host and definitive human host.

Disease pathology

Schistosome worms can live in vertebrate host for long time without severe manifestations of disease.

Female worms live in human portal veins depositing eggs in the intestines or bladder walls.

Eggs pass to the gut or bladder lumen and are voided in the faeces or urine.

Some eggs are trapped in the liver, intestines, bladder and other tissue sites of host.

Disease pathology

Schistosomiasis pathology due to granulomatous response to eggs trapped in host tissues .

Pathology caused by egg-derived antigens.

Liver - S. mansoni & S. japonicum Intestine – (hepatic and intestinal

schistosomiasis)

Bladder - S. haematobium (urinary schistosomisis)

Egg in trapped hepatic cells

Aggregation of mononuclear cells, neutrophils, basophils, macrophages, lymphocytes. Adapted from Parasitology Atlas

Hepatic Granuloma

Granuloma formation around the schistosome egg in hepatic cellsAdapted from Parasitology Atlas

Hepatic Granuloma

Advanced hepatic Granuloma around the parasite egg.

Urinary Granuloma

Granulomas around eggs lodged in urinary tract.

Challenges of schistosomiasis control

World Health Assembly resolutions WHA54.19 (2001) Required that by year 2010 regular treatment at appropriate intervals be offered to 75-100% of all school-age children living where schistosomisis, ascariasis, hookworm disease and trichuriasis have public health consequences.

Development of

Praziquante

l resistant

strains

•Praziquantel drug of choice for treatment.

•In-effective against immature parasites.

•Used in mass chemotherapy - S.S. Africa - accelerates drug resistance.

Need for

New drugs

•Development is hampered by the lack of interest among drug manufacturers in investing in limited market >>poor people>>

•More interested in veterinary antihelminthics- large market.

Re-infections in endemic

areas

•Despite 20yrs control efforts disease burden increasing.

•Praziquantel control programs have limitations.

•Mass treatment does not prevent re-infections.

•6 -8 months after chemotherapy prevalence returns to baseline level

Need for

anti-schistosom

e vaccin

e

•Need for Vaccines in combination with other control strategies.

•Many potential vaccine antigens in the past published.

•Only one entered clinical trials- 28-GST.

•Clinical efficacy of this vaccine still unknown.

• Need to explore new vaccine targets.

Increased schistosomiasis in developing

worlds

Climatic change

Increased dam

construction

Increased area under irrigation

Migration

Lack of

early

diagnostics

•Current methods based on egg detection in faeces or urine (Kato smear).

•Diagnosis after occurrence of disease pathology.

Need for new diagnostics

•Need to explore potential biomarkers.

•Need for improved techniques for diagnosis and prognosis.

To control schistosomiasis, there is need for;

New drugs

Vaccines

New diagnostics

Snail Vector control

What role can genomic information play in addressing these challenges?

Schistosome genomics

1994 WHO established Schistosoma genome sequencing project partnering with TIGR (S. mansoni) and CHGC (S. japonicum).

Project aims◦To promote chemotherapeutic targets◦and vaccine candidates.

2009 draft sequences of the two parasite have been published.

Understanding Schistosome

Biology

GenomicsWHO 1994

Transcriptomics

Metabolomics

Proteomics

Schistosome Genome

Schistosome transcriptom

e

Similarity search of

known drug targets in Medicinal Chemistry

DB

Identify parasite proteins matching

drug targets

Search DB of targets for human directed drugs

Identify significant matches to

present marketed

human drugs

Test on parasite culture

and animal models

Drug repositioning strategy for discovery of new anti-schistosome drugs

Examples of potential drugs identified using drug repositioning approach (Berriman et al., Nature ,2009)

Gene identifier Protein description

Potential drugs

Smp_005210 Histone deacetylase 1 (HDAC1)

Vorinostat

Smp_009030 Ribonucleoside-diphosphate reductase, a subunit, putative

Fludarabine phosphate

Smp_012930 Inosine-5-monophosphate dehydrogenase, putative

Mycophenolate mofetil, mycophenolic acid, ribavirin

Smp_015020 Na1,K1-ATPase a subunit (SNaK1)

Digoxin, digitoxin, acetyldigitoxin, deslanoside

Smp_040790 Cyclophilin B Cyclosporine

Smp_053220 Aldo-keto reductase Tolrestat

Smp_026560 Calmodulin, putative

Bepridil

Benefits of drug repositioning

Offers shortened development timelines.

Decreased risk as compounds already passed regulatory clinical trials with full toxicological & pharmacokinetic profiles.

Significant potential cost savings – important in the context of neglected diseases afflicting the poor

Vaccine targets discovery

Development and deployment of a vaccine is important for control of schistosomiasis.

Vaccine candidate must be accessible to host immune system.

Surface-exposed or exported.i.e. membrane proteins, e.g. Receptors,

some enzymes, ion-binding proteins, immuno-modulatory molecules.

Example- tegumental proteins in parasite.

Vaccine candidates targets Validation in animal models

Immunoinformatics predicts cell surface epitopes

Bioinformatics cellular location predictions and topology of selected

parasite proteins

Schistosome Genomes

Examples of potential vaccine candidates

Tetraspanins in the outer tegument- function as receptors of for host molecules.

Membrane proteins -calpin, annexin, Sm29

Biomarkers discovery using metabolomic approachControl of schistosomiasisis relies

upon continued surveillance of the disease.

Need for a robust diagnostic/prognostic technologies.

Use of metabolomics approaches using gene micro-array data.

Used identify patterns of biomarkers in parasite genes, proteins, and metabolites.

Metabolomic approach in diagnostic biomarkers discovery for neglected infectious diseases. (Denery et al., 2010 )

This technique has been used successfully to identify 14 diagnostic biomarkers for filariasis (ochorcerciasis)- a neglected parasitic disease.

Including - fatty acid/sterol lipid, Protein, hexacosenoic acid, pentacosenoic acid, fatty alcohol/aldehyde .

ConclusionGenomic information plays a critical role

in offering global insights in pathogenesis of schistosomiasis.

It also invaluable in accelerating discovery of new control targets such as drugs, vaccines and diagnostic biomarkers especially for neglected diseases such as schistosomiasis with limited funding.

Important tool for scientists in developing world, who need to set the pace in seeking control strategies to these diseases.

Acknowledgements

Combat Diseases of Poverty Consortium (CDPC).

Egerton University, Department of Biochemistry & Molecular Biology.Prof Moses Limo & Dr Paul Mireji

Dr Dorcas YoleInstitute of Primate Research, National Museums of Kenya.

Thank you.