Sheet nº 234
February 2006
A Leishmania parasite protein revealed
as a potential therapeutic target
Leishmaniases are serious tropical diseases,
endemic in 88 countries. No effective vaccine
is available to date and the existing range of
drugs is limited. After the discovery (1) of a
Leishmania gene coding for a protein that is
homologous to a specific protein family (silent
information regulator 2, SIR2), the subject of
much research effort, IRD researchers focused on its possible involvement in physiopathological effects induced by the parasite
infection. SIR2 appears essential for the parasite’s survival. This makes it an attractive therapeutic target.
a
b
c
Photos of the same macrophage, infected with L. infantum amastigotes: under
phase-contrast and after DNAstaining with propidium iodide
©IRD/Baptiste VERGNES
eishmaniases are endemic tropical
diseases that occur in more than 88 countries, all over the world except in
Australasia. They concern over 350 million
people. The pathogenic agents are protozoans
of the Leishmania genus, transmitted by a single
bite from an insect vector, the female of a bloodfeeding sandfly of the sub-family Phlebotominae,
to human and other mammalian hosts where
they live as intracellular parasites. Four types of
leishmaniasis can affect humans. Clinical symptoms are highly varied, but they all have serious
consequences and some are fatal. No effective
vaccines are available and efforts to control the
vectors are fraught with difficulties. The only
current therapeutic approach is based on
chemotherapy, but the medicines used at
present have many limitations. Not only are they
costly and rather toxic, but also they are hampe-
L
red by resistance developing among the parasites, mainly to antimony which after nearly 70
years still forms the basis of antileishmanial
treatment. Any discovery of new therapeutic
targets is therefore crucial for developing new
medicines against these parasitic infections,
which WHO has classified as priority diseases
(category 1 : re-emerging or uncontrolled infections) (www.who.int/tdr/)
Standard strategies for characterizing new antiparasitic compounds are based on empirical
approaches that consist in sorting out in vitro
which activities of natural or synthetic molecules
can attack the viability of the parasite. The action
mechanism would then be studied afterwards, if
at all. Now the array of modern tools of molecular
biological available can help identify candidate
parasite genes from which specific compounds
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might be synthesized that would inhibit the biological
action of the products of those genes. The targets are
usually genes or families of genes involved in a biochemical pathway that is indispensable for the parasite’s
survival (especially in its intracellular form) and which is
sufficiently different from those found in its host, or even
absent.
Some years ago, research investigations on the ageing
processes discovered that severe calorific restriction –
in other words, a drastic diet – extends the life expectancy of a great many animals. Recent data indicated
SIR2 to be a universal regulator of longevity in eucaryote organisms. Proteins of the SIR2 family are under
the scrutiny of intensive research, including studies on
carcinogenesis. Amember of this family of proteins was identified for the first time in 1996 in Leishmania major (1).
The growing interest for these proteins has led lRD
researchers, working with teams from INSERM and the
University of Porto in Portugal, to go further into the
biological functions of SIR2 and study its possible involvement in pathological physiological effects of parasite
infections. The team is therefore following up the
concept of inactivating the SIR2 gene of Leishmania
infantum, the pathogen of visceral leishmaniasis.
Experiments involving SIR2 gene deletion demonstrate
that it is essential for the parasites’ survival. This is the
first demonstration to date that an SIR2 gene is indispensable for the survival of an organism.
Redaction – IRD : Béatrice Le Brun
Translation : Nicholas Flay
Interestingly, when the parasite is obliged to express
only a minimal level of SIR2 protein it is incapable of
multiplying in the macrophage in vitro and during an
experimental infection in mice is gradually eliminated.
Working in a way far different from functions described
in other organisms, this SIR2 parasite protein could
now be considered as a potential new therapeutic
target. Seeking to support this hypothesis, the research
team tested the action of specific inhibitors of the SIR2
family proteins, such as sirtinol or nicotinamide. All
these manifested an antileishmanial activity on the
parasite stage that occurs in the vertebrate host.
These results are prompting combined research with
other institutes (2) to link efforts to exploit low-virulence
parasite clones with validation of the SIR2 gene product
as a therapeutic target in Leishmania and possibly
other parasites of the Trypanosomatidae family
(Trypanosoma cruzi and African trypanosomes).
The parasites with attenuated virulence might well be
killed rapidly in the host, which becomes a source of
antigens capable of stimulating the immune response.
Such an approach has the advantage of mimicking a
natural infection, usually eliciting a more effective
immune response than standard vaccines. By the
same token, enzyme studies and molecular modelling
of SIR2 can glean useful information for producing
specific inhibitors.
________________________
(1) Research Laboratory on Trypanosomatidae, INSERM Unité 415,
Institut Pasteur-Lille
(2) Le Centre de Biologie Structurale, CNRS UMR 5048, INSERM
U554, Montpellier and Faculty of Pharmacy and Institute of
Molecular and Cellular Biology, University of Porto, Portugal.
For futher information
CONTACTS:
Ali Ouaissi - UR 008 "Pathogénie des Trypanosomatidés", IRD, 911 avenue Agropolis, BP 5045, 34 032 Montpellier, France. Tel./Fax:
+33 (0)4 67 41 63 31. Email : ali.ouaissi@montp.inserm.fr
IRD Communication :
Sophie Nunziati (press officer), Tel.: +33 (0)1 48 03 75 19, Email: presse@paris.ird.fr
REFERENCES
Yahiaoui, B., Taibi, A. and Ouaissi A. A Leishmania major protein with extensive homology to silent information regulator 2 of Saccharomyces cerevisiae. Gene, 1996, 169: 115-8.
Vergnes B, Sereno D, Cordeiro-da-Silva A,Vanhille L,Tavares J, Madjidian-Sereno N, Depoix D, Monte-alegre
A and Ouaissi A. Targeted disruption of cytosolic SIR2 deacetylase discloses its essential role in Leishmania survival and proliferation. Gene, 2005, 363C:85-96.
Sereno D, Monte Allegre A, Sylvestre R, Vergnes B and Ouaissi A. In vitro antileishmanial activity of Nicotinamide.
Antimicrob Agents Chemother., 2005, 49: 8008-812.
ILLUSTRATIONS
Contact Indigo Base, IRD picture library, Claire Lissalde or Danièle Cavanna, Tel.: +33 (0)1 48 03 78 99, Email : indigo@paris.ird.fr
The illustrations can be viewed on: www.ird.fr/us/actualites/fiches/2004/fiche234.htm