MALARIA RESEARCH
IN THE POST-GENOMIC ERA
Elizabeth Ann Winzeler,
(2008) Nature, 455 (7214), pp. 751-756
Presenter: Reihaneh Rabbany
Presented in Bioinformatics Course (CMPUT 606),
Instructed by Prof. Guohui Lin,
Computing Science Department,
University of Alberta,
Winter 2009
WHAT IS IN THIS REVIEW?
In 2002 the genome sequence of Plasmodium
falciparum was completed
The parasite causing the most severe type of human
malaria
Genome-dependent research have provided new
discoveries which would lead to new therapies
This review is on these discoveries
MALARIA- HOW SIGNIFICANT?
Shaped the human genome
Evolutionary response providing protection
Negatively effect on human society
Decreasing productivity
Increasing poverty
515
million cases each year
MALARIA – CAUSE AND EFFECTS
Caused by Plasmodium, four species:
P. falciparum, P. vivax, P. ovale and P. malariae
Transmitted by the bites of
anopheline mosquitoes
P. falciparum
Has the greatest toll
Fever, anaemia, coma, death
Impaired ability to learn in survived children
MALARIA PARASITE’S LIFE CYCLE
MALARIA CONTROL - DRUGS
Some cheap and safe drugs that are still used
But their continued use poses widespread parasite
resistance
At present, World Health Organization is
recommending the use of a herbal drug
Parasite resistance in the rodent models
A few cases of treatment failure in human patients
The
need for continued drug discovery
research
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MALARIA CONTROL - VACCINE
Subunit vaccines
RTS,S
Based on P. falciparum protein
Is targeted for licensing in 2011
Reduced the number of severe cases
Children still developed malaria
Decrease malaria severity and morbidity
There are still more than 40 subunit vaccines in
development and 16 in clinical trials
Attenuated vaccines
Sporozoite are attenuated
less practical than single-subunit vaccines
efforts are being made to overcome its obstacles
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MALARIA CONTROL – VACCINE
Still don’t have a fully protective and licensed
malaria vaccine despite decades of effort
These are initiated decades ago
When researchers were limited by their ability to
work with malaria parasites in the laboratory
Thus vaccine research efforts were mostly focused on
a relatively small number of very abundant proteins
that could be easily studied
Now we are in genomic era
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MALARIA GENOMES - SEQUENCING
2002:
Complete genome sequence of P. falciparum
A partial sequence of rodent parasite,
2005:
sequences of several other rodent parasites
P. vivax (a human malaria parasite)
P. knowlesi (primarily a monkey parasite)
+ sequence of:
Human genome
Anopheles mosquito
New Candidates for drug and vaccine pipeline
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PLASMODIUM GENOMES
23–27 million bases
14 chromosomes
~5,500 genes
Rich in low-complexity regions
High A+T content
P. falciparum: 79.6%
P. vivax: 67.7%
Extreme A+T content has probably not too much to
do with the disease
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PLASMODIUM GENOMES (CONT.)
Differences between the species
P. falciparum: many of the multigene families
involved in immune evasion are located near the ends
of chromosomes
P. knowlesi: members of multigene families are
scattered across the chromosomes
77% of the proteins are conserved
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PLASMODIUM GENOMES – WE KNOW AS
LITTLE AS WE DO
Many of the identified genes do not have
homologues in commonly studied model
organisms and often lack a clear cellular function
We don’t know
The basis for sex determination and How parasites
become committed to sexual development
The liver stages and How the parasites home to the
liver but then pass through transverse some cells
while forming parasitophorous vacuoles in others
Parasite metabolism inside a human may differ
from parasite metabolism in laboratory culture
12
FUNCTIONAL STUDIES OF MALARIA
GENOMES
Functional genomics:
What different genes do for the organism?
Using microarrays or mass spectrometers
Analyzing expression pattern in different life
cycle stages to predict possible functions
if a gene shows a large induction during early liver
stage development, there is a good chance that this is
the time when its protein product will be required
Analysis of the parasite proteome from male and
female gametocytes has revealed genes
contributing to the differences of different sexes
PlasmoDB
New genetic tools for testing these predictions
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FUNCTIONAL STUDIES OF MALARIA
GENOMES
Good correlation between transcript and protein
abundance but In a number of cases genes are
transcribed but then not translated until the
organism has made the rapid transition between
warm- and cold-blooded hosts
transcripts needed for gamete formation in the
mosquito are produced in the mammalian host
Groups of genes with a probable involvement in
the parasite’s interaction with the mosquito
Could be candidates for transmission-blocking
vaccines
Prevent an infected individual from passing the
disease on to the next person
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GENOME-WIDE ANALYSIS OF ANTIGENIC
VARIATION
Genome-wide transcription studies
Expression analysis and genome sequence has
permitted the transcription of the 60 var genes
How antigenic variation in parasites may be regulated
One exceptionally abundant sporozoite protein in P.
berghei which was more immunogenic than some of
the historical antigens
how parasites evade the host immune system
Antigens derived from this protein are found in an
experimental vaccine
Identification of parasite genes that are specifically
transcribed while the parasite resides in the mosquito
salivary gland
Disruption of these genes has led to attenuated parasites
which are unable to colonize but induce a protective
immune response.
15
GENETIC DIVERSITY IN MALARIA
PARASITES
Change how genes involved in drug resistance
are discovered
Previously Identified through mapping studies or
Candidate gene approaches
Genome-dependent methods have revealed new
candidate genes that may be involved in drug
resistance
Studies of genetic variation revealed that a
universally effective single-subunit malaria
vaccine may be difficult to develop
vastly different rates of variability in different
parasite gene classes
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FROM THE GENOME TO CELL BIOLOGY
Import of nutrients and export of motif proteins
involved in immune evasion occurring
Also found in exported proteins from the plant
pathogen
the motif is attached to small proteins introduced
into the plant cytoplasm where they interfere with
the plant defense systems
A few seem to be transcribed in the early liver
stage like CSP
downregulating many genes involved in immune
signalling and upregulating other genes involved in
cell adhesion and possibly apoptosis
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FROM THE GENOME TO CELL BIOLOGY
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THE GENOME AND DRUG DISCOVERY
Recent drug discovery campaigns may be shifting
from the single-enzyme screening approaches to
cell-based methods where one can test for
inhibition of all essential proteins simultaneously
Still much work ahead: RTS,S and irradiated
sporozoite vaccines are both imperfect
Drug development: laboratory setting
If basic research continues to be a priority and if
support is sustained, new drugs and effective
vaccines are likely to be developed, and this could
make the goal of global malaria eradication
achievable
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QUESTIONS
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