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

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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 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

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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

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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

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

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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

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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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