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Pathogens (Basel, Switzerland) Jan 2020are obligate intracellular parasites known to have developed successful ways of efficient immunity evasion. Because of this, leishmaniasis, a disease caused by these...
are obligate intracellular parasites known to have developed successful ways of efficient immunity evasion. Because of this, leishmaniasis, a disease caused by these flagellated protists, is ranked as one of the most serious tropical infections worldwide. Neither prophylactic medication, nor vaccination has been developed thus far, even though the infection has usually led to strong and long-lasting immunity. In this paper, we describe a "suicidal" system established in , a human pathogen causing cutaneous leishmaniasis. This system is based on the expression and (de)stabilization of a basic phospholipase A2 toxin from the snake venom, which leads to the inducible cell death of the parasites in vitro. Furthermore, the suicidal strain was highly attenuated during macrophage infection, regardless of the toxin stabilization. Such a deliberately weakened parasite could be used to vaccinate the host, as its viability is regulated by the toxin stabilization, causing a profoundly reduced pathogenesis.
PubMed: 31991768
DOI: 10.3390/pathogens9020079 -
International Journal of Infectious... May 2020
PubMed: 32114198
DOI: 10.1016/j.ijid.2020.02.046 -
Virulence Dec 2021Catalase is one of the most abundant enzymes on Earth. It decomposes hydrogen peroxide, thus protecting cells from dangerous reactive oxygen species. The...
Catalase is one of the most abundant enzymes on Earth. It decomposes hydrogen peroxide, thus protecting cells from dangerous reactive oxygen species. The catalase-encoding gene is conspicuously absent from the genome of most representatives of the family Trypanosomatidae. Here, we expressed this protein from the locus using a novel bicistronic expression system, which relies on the 2A peptide of . We demonstrated that catalase-expressing parasites are severely compromised in their ability to develop in insects, to be transmitted and to infect mice, and to cause clinical manifestation in their mammalian host. Taken together, our data support the hypothesis that the presence of catalase is not compatible with the dixenous life cycle of , resulting in loss of this gene from the genome during the evolution of these parasites.
Topics: Animals; Catalase; Cells, Cultured; Female; Leishmania mexicana; Life Cycle Stages; Mice; Mice, Inbred BALB C; Protozoan Proteins; Psychodidae; Teschovirus; Virulence; Virulence Factors
PubMed: 33724149
DOI: 10.1080/21505594.2021.1896830 -
Current Opinion in Microbiology Dec 2022In eukaryotic cells, reversible attachment of ubiquitin and ubiquitin-like modifiers (Ubls) to specific target proteins is conducted by multicomponent systems whose... (Review)
Review
In eukaryotic cells, reversible attachment of ubiquitin and ubiquitin-like modifiers (Ubls) to specific target proteins is conducted by multicomponent systems whose collective actions control protein fate and cell behaviour in precise but complex ways. In trypanosomatids, attachment of ubiquitin and Ubls to target proteins regulates the cell cycle, endocytosis, protein sorting and degradation, autophagy and various aspects of infection and stress responses. The extent of these systems in trypanosomatids has been surveyed in recent reports, while in Leishmania mexicana, essential roles have been defined for many ubiquitin-system genes in deletion mutagenesis and life-cycle phenotyping campaigns. The first steps to elucidate the pathways of ubiquitin transfer among the ubiquitination components and to define the acceptor substrates and the downstream deubiquitinases are now being taken.
Topics: Ubiquitin; Ubiquitination; Proteins; Eukaryotic Cells; Autophagy
PubMed: 36099676
DOI: 10.1016/j.mib.2022.102202 -
Parasitology Sep 2021Telomeres are the ends of linear eukaryotic chromosomes facilitating the resolution of the ‘end replication and protection’ problems, associated with linearity. At...
Telomeres are the ends of linear eukaryotic chromosomes facilitating the resolution of the ‘end replication and protection’ problems, associated with linearity. At the nucleotide level, telomeres typically represent stretches of tandemly arranged telomeric repeats, which vary in length and sequence among different groups of organisms. Recently, a composition of the telomere-associated protein complex has been scrutinized in Trypanosoma brucei. In this work, we subjected proteins from that list to a more detailed bioinformatic analysis and delineated a core set of 20 conserved proteins putatively associated with telomeres in trypanosomatids. Out of these, two proteins (Ku70 and Ku80) are conspicuously missing in representatives of the genus Blastocrithidia, yet telomeres in these species do not appear to be affected. In this work, based on the analysis of a large set of trypanosomatids widely different in their phylogenetic position and life strategies, we demonstrated that telomeres of trypanosomatids are diverse in length, even within groups of closely related species. Our analysis showed that the expression of two proteins predicted to be associated with telomeres (those encoding telomerase and telomere-associated hypothetical protein orthologous to Tb927.6.4330) may directly affect and account for the differences in telomere length within the species of the Leishmania mexicana complex.
Topics: Leishmania mexicana; Telomere; Trypanosomatina
PubMed: 33612129
DOI: 10.1017/S0031182021000378 -
International Journal of Preventive... 2019Leishmaniasis is considered as a zoonotic infection and neglected tropical disease. treatment is not totally successful and imposes high expenditures, especially in... (Review)
Review
Leishmaniasis is considered as a zoonotic infection and neglected tropical disease. treatment is not totally successful and imposes high expenditures, especially in developing countries. Since the natural infection leads to the robust immunity in most of the human cases, many bodies of research have been focusing on vaccines, being capable to control infection. First generation vaccines (such as Leishmune and CaniLeish) have proved robust protective immunity in dogs. In human, recombinant vaccines, including Leish-F1 could confer some degrees of protective immunity against natural infection. Recently, ChAd63-KH DNA vaccine has been accomplished in providing prevention against infection; however, this vaccine should be further evaluated in other clinical trials.
PubMed: 31360342
DOI: 10.4103/ijpvm.IJPVM_116_18 -
Biomedicines Aug 2022Trypanosomiasis and leishmaniasis are neglected infections caused by trypanosomatid parasites. The first-line treatments have many adverse effects, high costs, and are...
Trypanosomiasis and leishmaniasis are neglected infections caused by trypanosomatid parasites. The first-line treatments have many adverse effects, high costs, and are prone to resistance development, hence the necessity for new chemotherapeutic options. In line with this, twenty five 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) derivatives were synthesized and evaluated in vitro for their anti-trypanosomatid activity. Ten and five compounds from this series showed IC50 ≤ 10 µM against the promastigote and the bloodstream stage of Leishmania mexicana and Trypanosoma brucei brucei, respectively. Overall, derivatives with pyrazole rings substituted with electron-withdrawing groups proved more active than those with electron-donating groups. The hits proved moderately selective towards L. mexicana and T. brucei (selectivity index, SI, compared to murine macrophages = 5−26). The exception was one derivative displaying an SI (>111−189) against T. brucei that surpassed, by >6-fold, the selectivity of the clinical drug nifurtimox (SI = 13−28.5). Despite sharing a common scaffold, the hits differed in their mechanism of action, with halogenated derivatives inducing a rapid and marked intracellular oxidative milieu in infective T. brucei. Notably, most of the hits presented better absorption, distribution, metabolism, and excretion (ADME) properties than the reference drugs. Several of the bioactive molecules herein identified represent a promising starting point for further improvement of their trypanosomatid potency and selectivity.
PubMed: 36009460
DOI: 10.3390/biomedicines10081913 -
Pathogens (Basel, Switzerland) Mar 2022Mast cells (MCs) play a crucial role during infections, which is transmitted through the bite of an infected sand fly that injects saliva together with the parasite....
Mast cells (MCs) play a crucial role during infections, which is transmitted through the bite of an infected sand fly that injects saliva together with the parasite. Sand fly saliva is a complex fluid that modulates the host immune response. In addition, hormonal factors modulate the host immune response and alter susceptibility to infections. Thus, to assess the impact of male sex hormones on the mast-cell (MC) response to infections, we orchiectomized male mice, infected them with the parasite in the presence of sand fly salivary proteins, and analyzed the inflammatory response of MCs. Our results showed that the MC response to the parasite and vector salivary proteins differed between orchiectomized and sham-operated mice. In orchiectomized mice, MC showed a retarded activation pattern, associated with slower degranulation and weaker TNF-α, histamine, and tryptase staining in response to the infection with combined with vector-salivary proteins, as compared to sham mice. Furthermore, neutrophil infiltration was slower in orchiectomized mice, and numbers of infected macrophages and lesion sizes were smaller. Our results show that, during infection, male sex hormones modulate the mast-cell response against the parasite and salivary proteins of the sand fly vector, inducing an intense inflammatory response. Their absence in orchiectomized mice retards the inflammatory response, enabling better control of the infection and slower disease progression.
PubMed: 35456073
DOI: 10.3390/pathogens11040398 -
IUBMB Life Nov 2019Toll-like receptors (TLRs) are a subset of pattern recognition receptors (PRR) in innate immunity and act as a connecting link between innate and adaptive immune... (Review)
Review
Toll-like receptors (TLRs) are a subset of pattern recognition receptors (PRR) in innate immunity and act as a connecting link between innate and adaptive immune systems. During Leishmania infection, the activation of TLRs influences the pathogen-specific immune responses, which may play a decisive role in determining the outcome of infection, toward elimination or survival of the pathogen. Antigen-presenting cells (APCs) of the innate immune system such as macrophages, dendritic cells (DCs), neutrophils, natural killer (NK) cells, and NKT cells express TLR2, which plays a crucial role in the parasite recognition and elicitation of immune responses in Leishmania infection. Depending on the infecting Leishmania species, the TLR2 pathways may result in a host-protective or a disease-exacerbating response. While Leishmania major and Leishmania donovani infections trigger TLR2-related host-protective and non-protective immune responses, Leishmania mexicana and Leishmania infantum infections are reported to elicit TLR2-mediated host-protective responses and Leishmania amazonensis and Leishmania braziliensis infections are reported to evoke a disease-exacerbating response. These findings illustrate that TLR2-related effector functions are diverse and may be exerted in a species- or strain-dependent manner. TLR2 agonists or antagonists may have therapeutic potentials to trigger the desired immune response during leishmaniasis. In this review, we discuss the TLR2-related immune responses during leishmaniasis and highlight the novel insights into the possible role of TLR2-driven resistance or susceptibility to Leishmania.
Topics: Animals; Antiparasitic Agents; Cytokines; Dendritic Cells; Drug Resistance, Neoplasm; Host-Parasite Interactions; Humans; Immunity, Innate; Leishmania; Leishmaniasis; Macrophages; Signal Transduction; Toll-Like Receptor 2
PubMed: 31329370
DOI: 10.1002/iub.2129 -
Biomedica : Revista Del Instituto... Jun 2019Knowledge of the geographical distribution of Leishmania species allows guiding the sampling to little-studied areas and implementing strategies to define risk zones and... (Review)
Review
INTRODUCTION
Knowledge of the geographical distribution of Leishmania species allows guiding the sampling to little-studied areas and implementing strategies to define risk zones and priority areas for control.
OBJECTIVE
Given that there is no publication that collects this information, the search, review, and compilation of the available scientific literature that has identified species in Colombia is presented in this paper.
MATERIALS AND METHODS
A bibliographic search was performed in PubMed, Web of Knowledge, Google Scholar, SciELO and LILACS with the terms "(Leishmania OR Leishmaniasis) AND species AND Colombia", without restrictions on publication year, language or infected organism; records of national scientific events and repositories of theses from Colombian universities were also included.
RESULTS
Eighty-six scientific documents published between 1985 and 2017 were found in which the species of Leishmania and their geographical origin were indicated. The species reported, in descending order of frequency, were: Leishmania (Viannia) panamensis, L. (V.) braziliensis, L. (V.) guyanensis, L. (Leishmania) infantum, L. (L.) amazonensis, L. (L.) mexicana, L. (V.) colombiensis, L. (V.) lainsoni and L. (V.) equatorensis; the last three were found with the same frequency. Leishmania species were reported from 29 departments.
CONCLUSION
Information on the distribution of Leishmania species in Colombia is limited; therefore, it is necessary to gather existing data and propose studies that consolidate the distribution maps of Leishmania species in Colombia. This would allow the detection of areas where species have not been identified as well as the comparison of existing parasite and vector distributions.
Topics: Animals; Colombia; Disease Reservoirs; Geography, Medical; Humans; Insect Vectors; Leishmania; Leishmaniasis; Mammals; Parasitology; Psychodidae; Species Specificity
PubMed: 31529815
DOI: 10.7705/biomedica.v39i3.4312