Parasite Prolyl Oligopeptidases and the Challenge of Designing Chemotherapeuticals for Chagas Disease, Leishmaniasis and African Trypanosomiasis

Bastos, Izabela Marques Dourado; Motta, Flávia Nader; Grellier, P.; Santana, Jaime M.

doi:10.2174/09298673113209990121

Cited by 8 publications

(13 citation statements)

References 92 publications

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“…In order to further study the effect of deleting the TevPOP-like gene on IL-10 production, an in vitro assay using BALB/c mouse splenocytes showed that CD3 + T-lymphocytes are the major producers of IL-10 and their ability to secrete IL-10 is reduced when incubated with Δpop-like parasites as opposed to the wild-type strain. During Leishmania mexicana infections in C57BL/6 mice, T cell-derived IL-10 was observed during the chronic phase of infection as opposed to classical immune suppression by IL-10 producing macrophages or dendritic cells (Bastos et al 2013). These IL-10-producing T cells could be CD4 + CD25 + and FoxP3 + regulatory T cells, which suggests that wild-type parasites induce immune suppression at the onset of the infection.…”

Section: Discussionmentioning

confidence: 97%

“…Although POPs from different species share similar three-dimensional structures, divergences have been observed between species in terms of inhibition and the specificity of substrates that they hydrolyse (Kaszuba et al 2012;Bastos et al 2013). Whereas recombinant POPs from T. brucei and T. cruzi are capable of hydrolysing proline rich native collagen, recombinant POP from Schistosoma mansoni is unable to hydrolyse substrates such as human collagens type I and IV (Bastos et al 2005(Bastos et al , 2010Fajtová et al 2015).…”

Section: Discussionmentioning

confidence: 99%

“…that belong to the S9 prolyl oligopeptidase family of clan SC serine proteases have been identified as potential drug and vaccine targets due to their unique properties (Coetzer et al 2008;Bastos et al 2013). Members of this family of serine peptidases in T. brucei (TbbPOP) and T. cruzi (TcrPOP) hydrolyse peptides smaller than 3 kDa at the carboxyl end of proline and alanine residues https://www.cambridge.org/core/terms.…”

Section: Introductionmentioning

confidence: 99%

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Prolyl oligopeptidase-like deficient Trypanosoma evansi parasites are associated with reduced interleukin-10 concentrations in vivo and in vitro

et al. 2017

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The protozoan parasite Trypanosoma evansi is responsible for causing Surra in a variety of mammalian hosts over a wide geographical area. In the absence of an effective vaccine and increasing resistance to current chemotherapeutic agents, peptidases from the S9 prolyl oligopeptidase family have been identified as potential drug and vaccine targets. In order to understand the function of these peptidases during infection, three null mutant clones for prolyl oligopeptidase (Δpop), prolyl oligopeptidase-like (Δpop-like) and oligopeptidase B (Δopb) were generated in T. evansi RoTat 1.2 parasites and used for infection of mice. Mice inoculated with T. evansi Δpop-like mutants were able to survive longer than other groups of mice inoculated with Δpop, Δopb mutants or wild-type parasites. The regression analysis of plasma from mice-infected over time using Δpop-like mutants showed stable levels of interleukin-10 (IL-10) (non-significant slope, P = 0·171) and declining IL-1b levels (negative slope, P = 0·04) when compared with the wild-type control that demonstrated increasing levels of IL-10 and IL1b (P < 0·01 for both). Further analysis using mouse spleen cells in an in vitro 24 h incubation assay revealed that the percentage of IL-10 producing CD3 positive cells display significantly lower values when incubated with Δpop-like parasites than the wild-type clone (P = 0·002). These results suggest that prolyl oligopeptidase-like peptidase may play a role in immune responses during T. evansi infections by affecting interleukin concentrations in the host. IntroductionThe mechanically transmitted protozoan parasite Trypanosoma evansi, a causative agent of the disease called Surra, is geographically the most widely distributed member of the genus Trypanosoma and infects the widest range of mammalian hosts, including buffaloes, camels, cattle, pigs, dogs, horses and goats (Holland et al. 2003;Dargantes et al. 2009;Desquesnes et al. 2013;Salah et al. 2015). Trypanosoma evansi parasites are transmitted by bloodsucking flies (Tabanus and Stomoxys spp.) (Hoare, 1972;Sumba et al. 1998) and also by vampire bats in South America (Hoare, 1965). Unlike T. congolense, a haemoparasite that is strictly restricted to the host blood vessels, the absence of T. evansi in the bloodstream can still result in pathogenic symptoms from parasites that have invaded host tissue (Holland et al. 2003;Desquesnes et al. 2013). The symptoms associated with T. evansi infections differ depending on the susceptibility of the infected host and include anaemia, fever, loss of weight and productivity as well as abortion (Vickerman et al. 1993;Desquesnes et al. 2013). In classical trypanosome infections, most of the symptoms emerge when the host immune system targets infective parasites. Parasites that die as a result of the host immune response release biologically active products that have been associated with disease symptoms (Taylor and Authié, 2004;Antoine-Moussiaux et al. 2009). These toxins include enzymes such as trypanosome peptidases that hyd...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prolyl oligopeptidase-like deficient Trypanosoma evansi parasites are associated with reduced interleukin-10 concentrations in vivo and in vitro

et al. 2017

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“…brucei genome and retrieved one SPC3-like subunit (Tb927.5.1930). The SPC3 subunit is essential for the activity of the catalytic subunit (Sec11p) in yeast [ 36 ]. RIT-seq experiments indicate the T .…”

Section: Discussionmentioning

confidence: 99%

An Essential Signal Peptide Peptidase Identified in an RNAi Screen of Serine Peptidases of Trypanosoma brucei

et al. 2015

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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.

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“…Although many efforts have been made to prevent these diseases, vaccines have not been satisfactory, and the drugs developed up to date to treat them have been limited by low efficacy, toxicity, drug resistance, and high cost (Bastos et al, ). Therefore, the development of new molecules able to prevent and control these parasite infections is a constant challenge.…”

Section: Leishmaniasis: Medical Importance and Disease Phenotypementioning

confidence: 99%

NTPDase activities: possible roles on Leishmania spp infectivity and virulence

Paes-Vieira

Gomes-Vieira

Meyer‐Fernandes

2018

Cell Biology International

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Nucleoside triphosphate diphosphohydrolases (NTPDases) are enzymes that belong to the GDA1/CD39 protein superfamily. These enzymes catalyze the hydrolysis of ATP and ADP to the monophosphate form (AMP). Biochemical characterization of the nucleotidases/NTPDases from various types of cells, including those from plants, animals, and pathogenic organisms, has revealed the existence of several isoforms with different specificities with respect to divalent cations (magnesium, calcium, manganese, and zinc) and substrates. In mammals, the NTPDases play important roles in the regulation of thrombosis and inflammation. In parasites of the genus Leishmania, the causative agents of leishmaniasis, two NTPDase isoforms, termed NTPDase-1 and NTPDase-2 have been described. Independently of their cellular localization, whether cell-surface localized, secreted or targeted to other organelles, in some Leishmania species these NTPDases could be involved in parasite growth, infectivity, and virulence. Experimental evidence has suggested that the hydrolysis of ATP and ADP by parasite ecto-nucleotidases can down-modulate the host immune response. In this context, the present work provides an overview of recent works that show strong evidence not only of the involvement of the nucleotidases/NTPDases in Leishmania spp infectivity and virulence but also of the molecular mechanisms that lead to the success of the parasitic infection.

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Parasite Prolyl Oligopeptidases and the Challenge of Designing Chemotherapeuticals for Chagas Disease, Leishmaniasis and African Trypanosomiasis

Cited by 8 publications

References 92 publications

Prolyl oligopeptidase-like deficient Trypanosoma evansi parasites are associated with reduced interleukin-10 concentrations in vivo and in vitro

Prolyl oligopeptidase-like deficient Trypanosoma evansi parasites are associated with reduced interleukin-10 concentrations in vivo and in vitro

An Essential Signal Peptide Peptidase Identified in an RNAi Screen of Serine Peptidases of Trypanosoma brucei

NTPDase activities: possible roles on Leishmania spp infectivity and virulence

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