Transcript Exploring New Control targets Using Genomic Information

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 SubSaharan 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
 S. mansoni
 S. japonicum
 S. hematobium
species
hepatic & intestinal schistosomiasis
urinary schistosomiasis

Global epidemiology of schistosomiasis
(Adapted from CDC)
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
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  Intestine –
 Bladder -
S. mansoni & S. japonicum
(hepatic and intestinal schistosomiasis)
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.
Challenges of schistosomiasis control
World Health Assembly resolutions
WHA54.19 (2001)
Required that by year 2010 regular treatment
at appropriate intervals be offered to 75100% 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
Need for antischistosome
vaccine
• Despite 20yrs control efforts disease burden
increasing.
• Praziquantel control programs have
limitations.
• Mass treatment does not prevent reinfections.
• 6 -8 months after chemotherapy prevalence
returns to baseline level
• 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.
Climatic
change
Migration
Increased
schistosomiasis
in developing
worlds
Increased
area
under
irrigation
Increased
dam
constructi
on
• Current methods based on egg
detection in faeces or urine (Kato
smear).
Lack of early • Diagnosis after occurrence of
disease pathology.
diagnostics
• Need to explore potential
biomarkers.
for improved techniques for
Need for new • Need
diagnosis and prognosis.
diagnostics
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.

Genomics
WHO
1994
Proteomics
Understanding
Schistosome
Biology
Metabolo
mics
Transcript
omics
Drug repositioning strategy for discovery of new antischistosome drugs
Schistosome
Genome
Schistosome
transcriptome
Similarity
search of
known drug
targets in
Medicinal
Chemistry
DB
Test on
parasite
culture and
animal
models
Identify
significant
matches to
present
marketed
human drugs
Search DB of
targets for
human
directed drugs
Identify
parasite
proteins
matching
drug targets
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
Ribonucleosidediphosphate reductase, a
subunit, putative
Fludarabine phosphate
Smp_012930
Inosine-5monophosphate
dehydrogenase, putative
Mycophenolate mofetil,
mycophenolic acid,
ribavirin
Smp_015020
Na1,K1-ATPase a subunit Digoxin, digitoxin,
(SNaK1)
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, immunomodulatory molecules.
 Example- tegumental proteins in parasite.

Schistosome Genomes
Bioinformatics cellular location predictions and
topology of selected parasite proteins
Immunoinformatics
predicts cell surface epitopes
Vaccine candidates targets
Validation in animal models
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.
Thank you.