Secreted Trypanosome Cyclophilin Inactivates Lytic Insect Defense Peptides and Induces Parasite Calcineurin Activation and Infectivity

Kulkarni, Milind V.; Karafova, Anna; Kamysz, Wojciech; Schenkman, Sérgio; Pellé, Roger; McGwire, Bradford S.

doi:10.1074/jbc.m112.421057

Cited by 31 publications

(34 citation statements)

References 61 publications

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“…In contrast, rdEpi is resistant to the human complement system, interacts with macrophages in a similar manner to trypomastigotes (even though it does not exhibit the amastigote intracellular stage) and can also infect mice. Some recent data corroborate the notion that epimastigotes could be infective in vitro to mammalian cells (Kulkarni et al, 2013), but the present work is the first to shows the genesis of epimastigote forms that maintain infectivity even after several duplication cycles. Some could argue against the present data that rdEpi is simply a transitional stage in the differentiation of trypomastigotes to epimastigotes, which could explain its virulence.…”

Section: Discussionsupporting

confidence: 89%

Recently differentiated epimastigotes from Trypanosoma cruzi are infective to the mammalian host

Kessler

Contreras

Marliére

et al. 2017

Molecular Microbiology

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Trypanosoma cruzi, the etiologic agent of Chagas disease, has a complex life cycle in which four distinct developmental forms alternate between the insect vector and the mammalian host. It is assumed that replicating epimastigotes present in the insect gut are not infective to mammalian host, a paradigm corroborated by the widely acknowledged fact that only this stage is susceptible to the complement system. In the present work, we establish a T. cruzi in vitro and in vivo epimastigogenesis model to analyze the biological aspects of recently differentiated epimastigotes (rdEpi). We show that both trypomastigote stages of T. cruzi (cell-derived and metacyclic) are able to transform into epimastigotes (processes termed primary and secondary epimastigogenesis, respectively) and that rdEpi have striking properties in comparison to long-term cultured epimastigotes: resistance to complement-mediated lysis and both in vitro (cell culture) and in vivo (mouse) infectivity. Proteomics analysis of all T. cruzi stages reveled a cluster of proteins that were up-regulated only in rdEpi (including ABC transporters and ERO1), suggesting a role for them in rdEpi virulence. The present work introduces a new experimental model for the study of host-parasite interactions, showing that rdEpi can be infective to the mammalian host.

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Section: Discussionsupporting

confidence: 89%

Recently differentiated epimastigotes from Trypanosoma cruzi are infective to the mammalian host

Kessler

Contreras

Marliére

et al. 2017

Molecular Microbiology

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“…PP2B is involved in a number of different signaling pathways and so participates in some physical activities. In Trypanosoma , Cyclophilin–trialysin synergistically acts on parasites to activate calcineurin phosphatase signaling, which mediates cAMP recognition and evasion and adaptation of the parasite . Orrego et al .…”

Section: Introductionmentioning

confidence: 99%

DNA prime‐protein boost vaccine encoding HLA‐A2, HLA‐A24 and HLA‐DR1 restricted epitopes of CaNA2 against visceral leishmaniasis

Fan²,

Zhang

et al. 2018

Immunology

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Summary Visceral leishmaniasis is a tropical and neglected disease with an estimated 200 000–400 000 cases and 60 000 deaths worldwide each year. Currently, no clinically valid vaccine is available for this disease. In this study, we formulated DNA and protein vaccines encoding HLA‐A2, HLA‐A24 and HLA‐DR1 restricted epitopes of CaNA2 against visceral leishmaniasis. We predicted the secondary and tertiary structures, surface properties, subcellular localization, potential binding sites and HLA‐A2, HLA‐A24 and HLA‐DR1 restricted epitopes of CaNA2. The best candidate CpG ODN (2395, M362, D‐SL03 or 685) was screened out as a DNA vaccine adjuvant. We also prepared Kmp‐11 and Kmp‐11/CaNA2 DNA and protein vaccines, respectively, for comparison. BALB/c mice were immunized with a DNA prime‐protein boost immunization strategy and challenged with a newly isolated Leishmania strain from an individual with visceral leishmaniasis. The IgG antibody titers showed that our vaccine had strong immunogenicity with a long duration, especially cellular immunity. The spleen parasite burden of each group demonstrated that the CaNA2 vaccine had a certain immune protective effect on visceral leishmaniasis in BALB/c mice, and the amastigote reduction rate reached 76%. Preliminary safety tests confirmed the safety of the vaccine. Our work demonstrates that the HLA‐A2, HLA‐A24 and HLA‐DR1 restricted epitope CaNA2 DNA prime‐protein boost vaccine may be a safe and effective epitope vaccine candidate against visceral leishmaniasis.

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“…The authors were also able to show that Cyp19 and P6 in concert are able to activate the calcium-dependent phosphatase calcineurin, by an as yet unknown mechanism, and thereby increase the infectivity of the parasites. Moreover, the activating and protective effects of the Cyp19-P6 complex could be transferred successfully to L. major and Leishmania amazonensis strains when conditioned medium of either species was used, indicating that these are general virulence mechanisms of trypanosomatid parasites (163). It is still an open question whether the binding of Cyp19 to P6 or other proline-containing CAMPs resembles a simple receptor-ligand interaction mediated by a proline residue or whether the PPIase activity contributes to neutralization of P6 by isomerizing it from an active to an inactive form.…”

Section: Protozoan Ppiases In Virulencementioning

confidence: 96%

“…In a recent study, it was shown that cationic antimicrobial peptides (CAMPs), part of the innate defense system of the reduviid bug vector of T. cruzi, can stimulate this transition rather than having an antiparasitic action. Intriguingly, this activation is dependent on the presence of the secreted cyclophilin Cyp19 of the parasite (163). For their study, the authors focused on the model CAMP P6, which is the biologically active N-terminal part of trialysin of Triatoma infestans.…”

Section: Protozoan Ppiases In Virulencementioning

confidence: 99%

Microbial Peptidyl-Prolyl cis / trans Isomerases (PPIases): Virulence Factors and Potential Alternative Drug Targets

Ünal

Steinert

2014

Microbiol Mol Biol Rev

160

146

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SUMMARY Initially discovered in the context of immunomodulation, peptidyl-prolyl cis/trans isomerases (PPIases) were soon identified as enzymes catalyzing the rate-limiting protein folding step at peptidyl bonds preceding proline residues. Intense searches revealed that PPIases are a superfamily of proteins consisting of three structurally distinguishable families with representatives in every described species of prokaryote and eukaryote and, recently, even in some giant viruses. Despite the clear-cut enzymatic activity and ubiquitous distribution of PPIases, reports on solely PPIase-dependent biological roles remain scarce. Nevertheless, they have been found to be involved in a plethora of biological processes, such as gene expression, signal transduction, protein secretion, development, and tissue regeneration, underscoring their general importance. Hence, it is not surprising that PPIases have also been identified as virulence-associated proteins. The extent of contribution to virulence is highly variable and dependent on the pleiotropic roles of a single PPIase in the respective pathogen. The main objective of this review is to discuss this variety in virulence-related bacterial and protozoan PPIases as well as the involvement of host PPIases in infectious processes. Moreover, a special focus is given to Legionella pneumophila macrophage infectivity potentiator (Mip) and Mip-like PPIases of other pathogens, as the best-characterized virulence-related representatives of this family. Finally, the potential of PPIases as alternative drug targets and first tangible results are highlighted.

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Secreted Trypanosome Cyclophilin Inactivates Lytic Insect Defense Peptides and Induces Parasite Calcineurin Activation and Infectivity

Cited by 31 publications

References 61 publications

Recently differentiated epimastigotes from Trypanosoma cruzi are infective to the mammalian host

Recently differentiated epimastigotes from Trypanosoma cruzi are infective to the mammalian host

DNA prime‐protein boost vaccine encoding HLA‐A2, HLA‐A24 and HLA‐DR1 restricted epitopes of CaNA2 against visceral leishmaniasis

Microbial Peptidyl-Prolyl cis / trans Isomerases (PPIases): Virulence Factors and Potential Alternative Drug Targets

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