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      Proteinases as virulence factors in Leishmania spp. infection in mammals

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          Abstract

          Leishmania parasites cause human tegumentary and visceral infections that are commonly referred to as leishmaniasis. Despite the high incidence and prevalence of cases, leishmaniasis has been a neglected disease because it mainly affects developing countries. The data obtained from the analysis of patients’ biological samples and from assays with animal models confirm the involvement of an array of the parasite’s components in its survival inside the mammalian host . These components are classified as virulence factors. In this review, we focus on studies that have explored the role of proteinases as virulence factors that promote parasite survival and immune modulation in the mammalian host. Additionally, the direct involvement of proteinases from the host in lesion evolution is analyzed. The gathered data shows that both parasite and host proteinases are involved in the clinical manifestation of leishmaniasis. It is interesting to note that although the majority of the classes of proteinases are present in Leishmania spp., only cysteine-proteinases, metalloproteinases and, to a lesser scale, serine-proteinases have been adequately studied. Members from these classes have been implicated in tissue invasion, survival in macrophages and immune modulation by parasites. This review reinforces the importance of the parasite proteinases, which are interesting candidates for new chemo or immunotherapies, in the clinical manifestations of leishmaniasis.

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          Most cited references96

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          MEROPS: the peptidase database

          Peptidases, their substrates and inhibitors are of great relevance to biology, medicine and biotechnology. The MEROPS database (http://merops.sanger.ac.uk) aims to fulfil the need for an integrated source of information about these. The database has a hierarchical classification in which homologous sets of peptidases and protein inhibitors are grouped into protein species, which are grouped into families, which are in turn grouped into clans. The classification framework is used for attaching information at each level. An important focus of the database has become distinguishing one peptidase from another through identifying the specificity of the peptidase in terms of where it will cleave substrates and with which inhibitors it will interact. We have collected over 39 000 known cleavage sites in proteins, peptides and synthetic substrates. These allow us to display peptidase specificity and alignments of protein substrates to give an indication of how well a cleavage site is conserved, and thus its probable physiological relevance. While the number of new peptidase families and clans has only grown slowly the number of complete genomes has greatly increased. This has allowed us to add an analysis tool to the relevant species pages to show significant gains and losses of peptidase genes relative to related species.
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            Cysteine proteases of parasitic organisms.

            Cysteine proteases play numerous indispensable roles in the biology of parasitic organisms. Aside from previously known general catabolic functions and protein processing, cysteine proteases may be key to parasite immunoevasion, excystment/encystment, exsheathing and cell and tissue invasion. Parasite cysteine proteases are unusually immunogenic and have been exploited as serodiagnostic markers and vaccine targets. Although host homologues exist, parasite cysteine proteases have distinct structural and biochemical properties including, pH optima and stability, the alteration in peptide loops or domain extensions, diverse substrate specificity and cellular location. The disparate nature of parasite cysteine protease compared to the host orthologous proteins has opened opportunities for chemotherapy. This review will highlight recent research on the 'papain-like' class of cysteine proteases, the most abundant family, and the newly discovered class of asparaginyl-endopeptidases. Cysteine protease classification will be re-examined in light of the diversity uncovered within parasitic organisms.
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              The current status of zoonotic leishmaniases and approaches to disease control.

              Leishmaniases are a complex of world-wide diseases with a range of clinical and epidemiological features caused by Leishmania spp. of protozoan parasites. Among 15 well-recognised Leishmania species known to infect humans, 13 have zoonotic nature, which include agents of visceral, cutaneous and mucocutaneous forms of the disease in both the Old and New Worlds. Currently, leishmaniases show a wider geographic distribution and increased global incidence of human disease than previously known. Environmental, demographic and human behavioural factors contribute to the changing landscape of leishmaniasis, which includes increasing risk factors for zoonotic cutaneous leishmaniases and new scenarios associated with the zoonotic visceral leishmaniases. The latter consist of the northward spread of Leishmania infantum transmission in Europe and America, the identification of unusual mammal hosts, and the decline of HIV-Leishmania co-infections in southern Europe following the introduction of the highly active antiretroviral therapy. Few advances have been made in the surveillance and control of the zoonotic leishmaniasis, however a number of tools have been developed for the control of the canine reservoir of L. infantum. These include: (i) several canine vaccine candidates, in particular an FML Leishmania enriched fraction showing good clinical protection, has been registered in Brazil for veterinary use; (ii) a number of insecticide-based preparations have been specifically registered for dog protection against sand fly bites. Laboratory and field studies have shown improved efficacy of these preparations for both individual and mass protection.
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                Author and article information

                Journal
                Parasit Vectors
                Parasit Vectors
                Parasites & Vectors
                BioMed Central
                1756-3305
                2012
                7 August 2012
                : 5
                : 160
                Affiliations
                [1 ]Laboratório de Biologia Molecular e Doenças Endêmicas, IOC, Fiocruz, Avenida Brasil, 4365 Manguinhos Pavilhão Leônidas Deane – sala 209, CEP: 21040-900, Rio de Janeiro, RJ, Brasil
                Article
                1756-3305-5-160
                10.1186/1756-3305-5-160
                3436776
                22871236
                37ecb2ca-11ea-4b0d-b294-909592ad748e
                Copyright ©2012 Silva-Almeida et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 1 March 2012
                : 12 July 2012
                Categories
                Review

                Parasitology
                proteinase,protease,lesion,leishmania spp.,leishmaniasis
                Parasitology
                proteinase, protease, lesion, leishmania spp., leishmaniasis

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