Presentation on theme: "Schistosomiasis: Exploring Genomic Information for Control Stephen Gikuru Egerton University-Kenya Irish Forum for Global Health Conference 30 th Nov 2010,"— Presentation transcript:
Schistosomiasis: Exploring Genomic Information for Control Stephen Gikuru Egerton University-Kenya Irish Forum for Global Health Conference 30 th Nov 2010, NUIM
A public health problem A public health problem Neglected parasitic disease that ranks 2 nd 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 disease Prevalent 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 parasites Caused 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, Suriname S. Japonicum – Hepatic/intestinal Schistosomiasis- China, Indonesia, Philippines. S. haematobium- Urinary Schistosomiasis- Africa, Middle East Global epidemiology of schistosomiasis (Adapted from CDC)
Life Cycle of Schistosome Adapted from CDC 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 cells Adapted from Parasitology Atlas
Hepatic Granuloma Advanced hepatic Granuloma around the parasite egg.
Urinary Granuloma Granulomas around eggs lodged in urinary tract.
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 Praziquantel 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- schistosome vaccine 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 constructi on 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.
Schistosome Genome Schistosome transcriptome 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 identifierProtein descriptionPotential drugs Smp_005210Histone deacetylase 1 (HDAC1) Vorinostat Smp_009030Ribonucleoside- diphosphate reductase, a subunit, putative Fludarabine phosphate Smp_012930Inosine-5- monophosphate dehydrogenase, putative Mycophenolate mofetil, mycophenolic acid, ribavirin Smp_015020Na1,K1-ATPase a subunit (SNaK1) Digoxin, digitoxin, acetyldigitoxin, deslanoside Smp_040790Cyclophilin BCyclosporine Smp_053220Aldo-keto reductaseTolrestat Smp_026560Calmodulin, putativeBepridil
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 approach Control 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.
Conclusion Genomic 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 Yole Institute of Primate Research, National Museums of Kenya.