Mapping of Druggable Genomic Targets in Evolving Malaria Parasite - Plasmodium falciparum

1. Mapping of Druggable Genomic Targets in Evolving
Malaria Parasites
- JAMES SABU
17BCB0117
BIT1004
B2+TB2
09/03/18

2.  Researchers at University of California San Diego School of Medicine and
Penn State, with a consortium of colleagues across the country and
around the world, have used whole genome analyses and chemo genetics
to identify new drug targets and resistance genes in 262 parasite cell
lines of Plasmodium falciparum – the protozoan pathogen that cause
malaria – that are resistant to 37 diverse antimalarial compounds.
 The study, published in the January 12, 2018 issue of Science, confirmed
previously known genetic modifications that substantially contribute to
the parasites’ drug resistance, but also revealed new targets that deepen
understanding of the parasites’ underlying biology.

3.  P. falciparum is a unicellular protozoan transmitted to humans through
the bite of infected Anopheles mosquitos. It is responsible for
approximately half of all malaria cases. Malaria’s massively
disproportionate impact on human health – the World Health
Organization estimates there were 216 million cases worldwide and
445,000 deaths in 2016 – is due in part to the parasites’ particular
adeptness at changing genomes to evade and resist drug treatment
and the human immune system.

4.  P. falciparum normally proceeds in two forms, uncomplicated or
severe. In most occurrence the severe case is observed showing
symptoms such as cerebral malaria, which cause abnormal behaviour,
seizures, coma, or impairment of consciousness. Severe symptoms
also present anaemia due to destruction of red blood cells,
haemoglobinuria, acute respiratory distress, low blood pressure, acute
kidney failure, metabolic acidosis, and hypoglycaemia. These are all
due to organ failure and abnormalities in patient's blood or
metabolism.
 During a rare uncomplicated infection, symptoms appear flu-like. The
attack lasts roughly 6-10 hours presenting a cold stage, hot stage, and
sweat stage. During these stages one shows symptoms of fever, chills,
sweats, headache, nausea, vomiting, body ached, and malaise.

5.  The best line of defence against any form of malaria is preventative
treatment, antimalarial, taken properly before, during, and after
exposure to parasite.
 Treatment of P. falciparum depends on severity of infection as well as
location where the infection took place. Treatment can also vary due
to an individual’s age, weight, and pregnancy status.
 In uncomplicated malaria, the first line of defence includes
Artemisinin-based combination therapy (ACT). ACTs are used to
improve treatment by overcoming the resistance by using more then
one derivative of Artemisinin.
 The choice of which ACT to use depends on the region in which the
infection took place. This is due to the varying level of resistance
found in different areas. Non-ACTs such as sulfadoxine-pyrimethamin
with chloroquine can also be used but are considered to have a
limited sufficiency due to drug resistance.
 In severe malaria, the main focus is to keep the patient from dying.
Rapid clinical assessment and confirmation is key.

6. The 48-hour lifecycle of
Plasmodium falciparum
development in human red blood
cells. A team of researchers has
used whole genome analysis and
chemo genetics to identify new
drug targets and resistance genes in
the parasite.

7.  “A single human infection can result in a person containing upwards of a
trillion asexual blood stage parasites,” said senior author Elizabeth Winzeler,
professor of pharmacology and drug discovery in the Department of Pediatrics
at UC San Diego School of Medicine. "Even with a relatively slow random
mutation rate, these numbers confer extraordinary adaptability. In just a few
cycles of replication, the P. falciparum genome can acquire a random genetic
change that may render at least one parasite resistant to the activity of a
drug or human-encoded antibody.”
 Such rapid evolution poses significant challenges to controlling the disease,
said researchers, but it can also be exploited in laboratory studies to
document precisely how the parasite evolves in the presence of known
antimalarials to create drug resistance. It can also be used to reveal new drug
targets.

8. Colorized micrograph of Plasmodium
falciparum.

9. This photomicrograph of a blood
smear contains a macro- and
microgametocyte of the
Plasmodium falciparum parasite.

10.  In short, these results provide a key link to understanding how malaria
parasites respond metabolically to drug pressure in the short term and they
also allow us to connect how this pressure is relieved through genomic
mutations that lead to resistance in the parasites.
 This knowledge could aid in the design of future antimalarial drugs that may
slow the development of resistance.
THANK YOU !!