Upload
albert-jordan
View
217
Download
1
Tags:
Embed Size (px)
Citation preview
MALARIA RESEARCH IN THE POST-GENOMIC ERA
Presenter: Reihaneh RabbanyPresented in Bioinformatics Course (CMPUT 606),
Instructed by Prof. Guohui Lin,
Computing Science Department,
University of Alberta,
Winter 2009
Elizabeth Ann Winzeler, (2008) Nature, 455 (7214), pp. 751-756
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 societyDecreasing productivityIncreasing 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. falciparumHas 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 6
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
7
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
8
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 genomeAnopheles mosquito
New Candidates for drug and vaccine pipeline9
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
10
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
11
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
13
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
14
GENOME-WIDE ANALYSIS OF ANTIGENIC VARIATION Genome-wide transcription studies
how parasites evade the host immune system 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 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 classes16
FROM THE GENOME TO CELL BIOLOGY
17
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
FROM THE GENOME TO CELL BIOLOGY
18
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
19
QUESTIONS
20