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      Impact of Genetic Diversity and Genome Plasticity of Leishmania spp. in Treatment and the Search for Novel Chemotherapeutic Targets

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          Abstract

          Leishmaniasis is one of the major public health concerns in Latin America, Africa, Asia, and Europe. The absence of vaccines for human use and the lack of effective vector control programs make chemotherapy the main strategy to control all forms of the disease. However, the high toxicity of available drugs, limited choice of therapeutic agents, and occurrence of drug-resistant parasite strains are the main challenges related to chemotherapy. Currently, only a small number of drugs are available for leishmaniasis treatment, including pentavalent antimonials (Sb V), amphotericin B and its formulations, miltefosine, paromomycin sulphate, and pentamidine isethionate. In addition to drug toxicity, therapeutic failure of leishmaniasis is a serious concern. The occurrence of drug-resistant parasites is one of the causes of therapeutic failure and is closely related to the diversity of parasites in this genus. Owing to the enormous plasticity of the genome, resistance can occur by altering different metabolic pathways, demonstrating that resistance mechanisms are multifactorial and extremely complex. Genetic variability and genome plasticity cause not only the available drugs to have limitations, but also make the search for new drugs challenging. Here, we examined the biological characteristics of parasites that hinder drug discovery.

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          Most cited references137

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          The relationship between leishmaniasis and AIDS: the second 10 years.

          To date, most Leishmania and human immunodeficiency virus (HIV) coinfection cases reported to WHO come from Southern Europe. Up to the year 2001, nearly 2,000 cases of coinfection were identified, of which 90% were from Spain, Italy, France, and Portugal. However, these figures are misleading because they do not account for the large proportion of cases in many African and Asian countries that are missed due to a lack of diagnostic facilities and poor reporting systems. Most cases of coinfection in the Americas are reported in Brazil, where the incidence of leishmaniasis has spread in recent years due to overlap with major areas of HIV transmission. In some areas of Africa, the number of coinfection cases has increased dramatically due to social phenomena such as mass migration and wars. In northwest Ethiopia, up to 30% of all visceral leishmaniasis patients are also infected with HIV. In Asia, coinfections are increasingly being reported in India, which also has the highest global burden of leishmaniasis and a high rate of resistance to antimonial drugs. Based on the previous experience of 20 years of coinfection in Europe, this review focuses on the management of Leishmania-HIV-coinfected patients in low-income countries where leishmaniasis is endemic.
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            TriTrypDB: a functional genomic resource for the Trypanosomatidae

            TriTrypDB (http://tritrypdb.org) is an integrated database providing access to genome-scale datasets for kinetoplastid parasites, and supporting a variety of complex queries driven by research and development needs. TriTrypDB is a collaborative project, utilizing the GUS/WDK computational infrastructure developed by the Eukaryotic Pathogen Bioinformatics Resource Center (EuPathDB.org) to integrate genome annotation and analyses from GeneDB and elsewhere with a wide variety of functional genomics datasets made available by members of the global research community, often pre-publication. Currently, TriTrypDB integrates datasets from Leishmania braziliensis, L. infantum, L. major, L. tarentolae, Trypanosoma brucei and T. cruzi. Users may examine individual genes or chromosomal spans in their genomic context, including syntenic alignments with other kinetoplastid organisms. Data within TriTrypDB can be interrogated utilizing a sophisticated search strategy system that enables a user to construct complex queries combining multiple data types. All search strategies are stored, allowing future access and integrated searches. ‘User Comments’ may be added to any gene page, enhancing available annotation; such comments become immediately searchable via the text search, and are forwarded to curators for incorporation into the reference annotation when appropriate.
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              Post-transcriptional regulation of gene expression in trypanosomes and leishmanias.

              Gene expression in Kinetoplastids is very unusual in that the open reading frames are arranged in long polycistronic arrays, monocistronic mRNAs being created by post-transcriptional processing. Thus the regulation of gene expression is post-transcriptional. We here discuss recent results concerning the enzymes required for mRNA degradation, and components of the translation initiation machinery, and how both are regulated.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/1580159
                URI : https://loop.frontiersin.org/people/1200063
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                24 January 2022
                2022
                : 12
                : 826287
                Affiliations
                [1] Grupo de Genômica Funcional de Parasitos – Instituto René Rachou, Fundação Oswaldo Cruz , Belo Horizonte, Brazil
                Author notes

                Edited by: Luiz Tosi, University of São Paulo, Brazil

                Reviewed by: Karunakaran Kalesh, Durham University, United Kingdom

                *Correspondence: Silvane Maria Fonseca Murta, silvane.murta@ 123456fiocruz.br

                This article was submitted to Parasite and Host, a section of the journal Frontiers in Cellular and Infection Microbiology

                Article
                10.3389/fcimb.2022.826287
                8819175
                35141175
                d8528cb7-ebe8-4f39-9ef5-2c41c6bea064
                Copyright © 2022 Santi and Murta

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 November 2021
                : 04 January 2022
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 138, Pages: 9, Words: 3571
                Categories
                Cellular and Infection Microbiology
                Mini Review

                Infectious disease & Microbiology
                leishmania,chemotherapy,drug resistance,genetic diversity,genome plasticity

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