Schistosoma mansoni Sirtuins: characterization and potential as chemotherapeutic targets.
BACKGROUND
The chemotherapy of schistosomiasis currently depends on the use of a single drug, praziquantel. In order to develop novel chemotherapeutic agents we are investigating enzymes involved in the epigenetic modification of chromatin. Sirtuins are NAD+ dependent lysine deacetylases that are involved in a wide variety of cellular processes including histone deacetylation, and have been demonstrated to be therapeutic targets in various pathologies, including cancer.


RESULTS
In order to determine whether Schistosoma mansoni sirtuins are potential therapeutic targets we first identified and characterized their protein sequences. Five sirtuins (SmSirt) are encoded in the S. mansoni genome and phylogenetic analysis showed that they are orthologues of mammalian Sirt1, Sirt2, Sirt5, Sirt6 and Sirt7. Both SmSirt1 and SmSirt7 have large insertion in the catalytic domain compared to their mammalian orthologues. SmSirt5 is the only mitochondrial sirtuin encoded in the parasite genome (orthologues of Sirt3 and Sirt4 are absent) and transcripts corresponding to at least five splicing isoforms were identified. All five sirtuins are expressed throughout the parasite life-cycle, but with distinct patterns of expression. Sirtuin inhibitors were used to treat both schistosomula and adult worms maintained in culture. Three inhibitors in particular, Sirtinol, Salermide and MS3 induced apoptosis and death of schistosomula, the separation of adult worm pairs, and a reduction in egg laying. Moreover, Salermide treatment led to a marked disruption of the morphology of ovaries and testes. Transcriptional knockdown of SmSirt1 by RNA interference in adult worms led to morphological changes in the ovaries characterized by a marked increase in mature oocytes, reiterating the effects of sirtuin inhibitors and suggesting that SmSirt1 is their principal target.
Our data demonstrate the potential of schistosome sirtuins as therapeutic targets and validate screening for selective sirtuin inhibitors as a strategy for developing new drugs against schistosomiasis.
Center for Infection and Immunity of Lille (CIIL), INSERM U1019 - CNRS UMR 8204, Université Lille Nord de France, Institut Pasteur de Lille, Lille, France.
Julien
J
Lancelot
Stéphanie
S
Caby
Florence
F
Dubois-Abdesselem
Mathieu
M
Vanderstraete
Jacques
J
Trolet
Guilherme
G
Oliveira
Franz
F
Bracher
Manfred
M
Jung
Raymond J
RJ
Pierce
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015801:Helminth Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D021261:Parasitic Sensitivity Tests; D010802:Phylogeny; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000235:genetics; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
D000871:Anthelmintics; D004791:Enzyme Inhibitors; D015801:Helminth Proteins; D037761:Sirtuins