Article

Leishmania infantum chagasi: A genome-based approach to identification of excreted/secreted proteins

Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Experimental Parasitology (Impact Factor: 1.64). 12/2010; 126(4):582-91. DOI: 10.1016/j.exppara.2010.06.011
Source: PubMed

ABSTRACT

The parasitic protozoan, Leishmania, survives in harsh environments within its mammalian and sand fly hosts. Secreted proteins likely play critical roles in the parasite's interactions with its environment. As a preliminary identification of the spectrum of potential excreted/secreted (ES) proteins of Leishmania infantum chagasi (Lic), a causative agent of visceral leishmaniasis, we used standard algorithms to screen the annotated L. infantum genome for genes whose predicted protein products have an N-terminal signal peptide and lack transmembrane domains and membrane anchors. A suite of 181 candidate ES proteins were identified. These included several that were documented in the literature to be released by other Leishmania spp. Six candidate ES proteins were selected for further validation of their expression and release by different parasite stages. We found both amastigote-specific and promastigote-specific released proteins. The ES proteins of Lic are candidates for future studies of parasite virulence determinants and host protective immunity.

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Available from: Selma M B Jeronimo, Nov 12, 2014
    • "These proteins play important role in the virulence of Leishmania parasite owing to their active participation in the infection and suppression of host immune system. Since these proteins are important in the pathogenesis of leishmaniasis hence it is expected that they could be exploited for inducing long-lasting immunity against leishmaniasis (DebRoy et al., 2010; Gour et al., 2012). Gour et al. (2012) examined a series of 17 excreted/ secreted proteins obtained from in vitro culture of L. donovani promastigotes as antigen for immunostimulant activity. "
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    ABSTRACT: Visceral leishmaniasis, which is also known as Kala-Azar, is one the most severe neglected tropical diseases recognized by World Health Organization (WHO). The threat of this debilitating disease is continued due to unavailability of promising drug therapy or human vaccine. An extensive research is undergoing to develop a promising vaccine to prevent this devastating disease. In this review we compiled the findings of recent research with a view to facilitate knowledge on experimental vaccinology for visceral leishmaniasis. Various killed or attenuated parasite based first generation vaccines, second generation vaccines based on antigenic protein or recombinant protein, and third generation vaccines derived from antigen-encoding DNA plasmids including heterologous prime-boost Leishmania vaccine have been examined for control and prevention of visceral leishmaniasis. Vaccines based on recombinant protein and antigen-encoding DNA plasmids have given promising results and few vaccines including Leishmune®, Leishtec, and CaniLeish® has been licensed for canine visceral leishmaniasis. A systematic investigation of these vaccine candidates can lead to development of promising vaccine for human visceral leishmaniasis, most probably in near future. Copyright © 2015. Published by Elsevier B.V.
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    • "In another recently study, L. infantum chagasi-excreted/secreted proteins were predicted using a genome-based approach (DebRoy et al., 2010). This was done screening the annotated L. infantum genome for genes, whose predicted protein products have an Nterminal secretion signal peptide and lack transmembrane domains and membrane anchors. "
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    • "However, of the seven reports on Leishmania secreted proteins, only one found that a large proportion of the secreted proteins identified contained an N-terminal secretion signal peptide for classical secretion (Paape et al., 2010). In all of the remaining reports, the authors observed the opposite to be true, with a majority of secretome proteins lacking a secretion signal peptide (Revest et al., 2008; Silverman et al., 2008, 2010a; DebRoy et al., 2010; Kima et al., 2010; Hassani et al., 2011). Three of the seven reports which investigated alternative mechanisms of secretion identified vesicles secreted by Leishmania (Silverman et al., 2008, 2010a; Hassani et al., 2011). "
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    ABSTRACT: Herein, we review evidence supporting a role for Leishmania exosomes during early infection. We suggest a model in which Leishmania secreted microvesicles released into the extracellular milieu deliver effector cargo to host target cells. This cargo mediates immunosuppression and functionally primes host cells for Leishmania invasion. Leishmania ssp. release microvesicles and the amount of vesicle release and the specific protein cargo of the vesicles is sensitive to changes in environmental conditions that mimic infection. Leishmania exosomes influence the phenotype of treated immune cells. For example, wild-type (WT) exosomes attenuate interferon-γ-induced pro-inflammatory cytokine production (TNF-α) by Leishmania-infected monocytes while conversely enhancing production of the anti-inflammatory cytokine IL-10. The Leishmania proteins GP63 and elongation factor-1α (EF-1α) are found in secreted vesicles and are likely important effectors responsible for these changes in phenotype. GP63 and EF-1α access host cell cytosol and activate multiple host protein-tyrosine phosphatases (PTPs). Activation of these PTPs negatively regulates interferon-γ signaling and this prevents effective expression of the macrophage microbicidal arsenal, including TNF-α and nitric oxide. In addition to changing macrophage phenotype, WT vesicles dampen the immune response of monocyte-derived dendritic cells and CD4+ T lymphocytes. This capacity is lost when the protein cargo of the vesicles is modified, specifically when the amount of GP63 and EF-1α in the vesicles is reduced. It appears that exosome delivery of effector proteins results in activation of host PTPs and the negative regulatory effects of the latter creates a pro-parasitic environment. The data suggest that Leishmania exosomes secreted upon initial infection are capable of delivering effector cargo to naïve target cells wherein the cargo primes host cells for infection by interfering with host cell signaling pathways.
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