Abstract
The serine peptidases of Trypanosoma brucei have been viewed as potential drug targets. In particular, the S9 prolyl oligopeptidase subfamily is thought to be a good avenue for drug discovery. This is based on the finding that some S9 peptidases are secreted and active in the mammalian bloodstream, and that they are a class of enzyme against which drugs have successfully been developed. We collated a list of all serine peptidases in T. brucei, identifying 20 serine peptidase genes, of which nine are S9 peptidases. We screened all 20 serine peptidases by RNAi to determine which, if any, are essential for bloodstream form T. brucei survival. All S9 serine peptidases were dispensable for parasite survival in vitro, even when pairs of similar genes, coding for oligopeptidase B or prolyl oligopeptidase, were targeted simultaneously. We also found no effect on parasite survival in an animal host when the S9 peptidases oligopeptidase B, prolyl oligopeptidase or dipeptidyl peptidase 8 were targeted. The only serine peptidase to emerge from the RNAi screen as essential was a putative type-I signal peptide peptidase (SPP1). This gene was essential for parasite survival both in vitro and in vivo. The growth defect conferred by RNAi depletion of SPP1 was rescued by expression of a functional peptidase from an RNAi resistant SPP1 gene. However, expression of catalytically inactive SPP1 was unable to rescue cells from the SPP1 depleted phenotype, demonstrating that SPP1 serine peptidase activity is necessary for T. brucei survival.
Highlights
Human African Trypanosomiasis (HAT) is a disease of the developing world that is fatal if left untreated
We found 20 individual genes representing serine peptidases from six families in the T. brucei genome (Table 1)
Animals were euthanised after this point, as parasiteamia levels rose above the humane threshold of 1 x 108 cells ml-1. These results indicate that a reduction in either Oligopeptidase B (OPB)/OPB-like or prolyl oligopeptidase (POP)/POP-like peptidases has no effect on the progression of infection in mice, either individually or in concert
Summary
Human African Trypanosomiasis (HAT) is a disease of the developing world that is fatal if left untreated. While the improved situation is encouraging, there is PLOS ONE | DOI:10.1371/journal.pone.0123241 March 27, 2015
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