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Medicinal Chemistry (Shariqah (United... 2022Leishmaniasis is a worldwide health problem, highly endemic in developing countries. Among the four main clinical forms of the disease, visceral leishmaniasis is the...
BACKGROUND
Leishmaniasis is a worldwide health problem, highly endemic in developing countries. Among the four main clinical forms of the disease, visceral leishmaniasis is the most severe, fatal in 95% of cases. The undesired side-effects from first-line chemotherapy and the reported drug resistance search for effective drugs that can replace or supplement those currently used in an urgent need. Aminoguanidine hydrazones (AGH's) have been explored for exhibiting a diverse spectrum of biological activities, in particular the antileishmanial activity of MGBG. The bioisosteres thiosemicarbazones (TSC's) offer a similar biological activity diversity, including antiprotozoal effects against Leishmania species and Trypanosoma cruzi.
OBJECTIVES
Considering the impact of leishmaniasis worldwide, this work aimed to design, synthesize, and perform a screening upon L. chagasi amastigotes and for the cytotoxicity of the small "inhouse" library of both AGH and TSC derivatives and their structurally-related compounds.
METHODS
A set of AGH's (3-7), TSC's (9, 10), and semicarbazones (11) were initially synthesized. Subsequently, different semi-constrained analogs were designed and also prepared, including thiazolidines (12), dihydrothiazines (13), imidazolines (15), pyrimidines (16, 18) azines (19, 20), and benzotriazepinones (23-25). All intermediates and target compounds were obtained with satisfactory yields and exhibited spectral data consistent with their structures. All final compounds were evaluated against L. chagasi amastigotes and J774.A1 cell line. Molecular docking was performed towards trypanothione reductase using GOLD software.
RESULTS
The AGH's 3i, 4a, and 5d, and the TSC's 9i, 9k, and 9o were selected as valuable hits. These compounds presented antileishmanial activity compared with pentamidine, showing ICvalues ranged from 0.6 to 7.27 μM, maximal effects up to 55.3%, and satisfactory SI values (ranged from 11 to 87). On the other hand, most of the resulting semi-constrained analogs were found cytotoxic or presented reduced antileishmanial activity. In general, TSC class is more promising than its isosteric AGH analogs, and the beneficial aromatic substituent effects are not similar in both series. In silico studies have suggested that these hits are capable of inhibiting the trypanothione reductase from the amastigote forms.
CONCLUSION
The promising antileishmanial activity of three AGH's and three TSC's was characterized. These compounds presented antileishmanial activity compared with PTD, showing IC50 values ranged from 0.6 to 7.27 μM, and satisfactory SI values. Further pharmacological assays involving other Leishmania strains are in progress, which will help choose the best hits for in vivo experiments.
Topics: Guanidines; Hydrazones; Leishmania infantum; Molecular Docking Simulation; Structure-Activity Relationship; Thiosemicarbazones
PubMed: 33593264
DOI: 10.2174/1573406417666210216154428 -
Scientific Reports Feb 2020Leishmaniases are neglected tropical diseases and Leishmania (Leishmania) infantum and Leishmania (Viannia) braziliensis are the most important causative agents of...
Leishmaniases are neglected tropical diseases and Leishmania (Leishmania) infantum and Leishmania (Viannia) braziliensis are the most important causative agents of leishmaniases in the New World. These two parasite species may co-circulate in a given endemic area but their interactions in the vector have not been studied yet. We conducted experimental infections using both single infections and co-infections to compare the development of L. (L.) infantum (OGVL/mCherry) and L. (V.) braziliensis (XB29/GFP) in Lutzomyia longipalpis and Lutzomyia migonei. Parasite labelling by different fluorescein proteins enabled studying interspecific competition and localization of different parasite species during co-infections. Both Leishmania species completed their life cycle, producing infective forms in both sand fly species studied. The same happens in the co infections, demonstrating that the two parasites conclude their development and do not compete with each other. However, infections produced by L. (L.) infantum reached higher rates and grew more vigorously, as compared to L. (V.) braziliensis. In late-stage infections, L. (L.) infantum was present in all midgut regions, showing typical suprapylarian type of development, whereas L. (V.) braziliensis was concentrated in the hindgut and the abdominal midgut (peripylarian development). We concluded that both Lu. migonei and Lu. longipalpis are equally susceptible vectors for L. (L.) infantum, in laboratory colonies. In relation to L. (V.) braziliensis, Lu. migonei appears to be more susceptible to this parasite than Lu. longipalpis.
Topics: Animals; Digestive System; Female; Insect Vectors; Leishmania braziliensis; Leishmania infantum; Life Cycle Stages; Psychodidae
PubMed: 32108151
DOI: 10.1038/s41598-020-60600-7 -
Acta Tropica May 2022Canine leishmaniosis is a vector-borne disease caused by Leishmania parasites. Serological methods are the most common tests used for the diagnosis. This study aimed to...
Canine leishmaniosis is a vector-borne disease caused by Leishmania parasites. Serological methods are the most common tests used for the diagnosis. This study aimed to evaluate and compare different serological commercial immunochromatographic rapid tests available in Spain to detect anti-Leishmania canine antibodies. The immunochromatographic tests were evaluated in different groups of dogs (healthy seronegative dogs (n = 21), naturally-sick dogs with moderate anti-Leishmania antibodies (n = 39), naturally-sick dogs with high anti-Leishmania antibodies (n = 37), dogs with the serological result of other pathogens infection (n = 20) and exposed dogs (n = 33)) admitted to the Veterinary Teaching Hospital of the University of Zaragoza (Spain) according to the clinical information sent with the sample to the laboratory for diagnostic purposes. The serology status was also routinely recorded through an in-house enzyme-linked immunosorbent assay (ELISA) and an in-house indirect immunofluorescence test (IFAT). The qualitative commercial serological immunochromatographic tests used were: FASTest LEISH, Uranotest Leishmania, Uranotest Leishmania 2.0, Speed Leish K, Witness Leishmania, and DFV Test Leishmania. Performance measures analyzed for each test were: sensitivity, specificity, and area under the receiver-operating (ROC) curve. The maximum specificity (1.00) was attained for Uranotest Leishmania and DFT Test Leishmania, followed by FASTest LEISH (0.98), Uranotest Leishmania 2.0 (0.98), Speed Leish K (0.98), and Witness Leishmania (0.95). The maximum sensitivity was attained for FASTest LEISH (1.00), followed by Uranotest 2.0 (0.97), Speed Leish K (0.97), Uranotest (0.96), and the lowest results with Witness (0.84) and DFV Test (0.59). Regarding the ROC curve, the maximum value was attained with the FASTest LEISH (0.99), followed by Uranotest (0.98), Uranotest 2.0 (0.97), Speed Leish K (0.97), Witness (0.90), and the lowest result with DFV Test (0.79). Efforts in the field of diagnosis should focus on establishing a commercial immunochromatographic test with high sensitivity and specificity with a reasonable cost-benefit balance.
Topics: Animals; Antibodies, Protozoan; Dog Diseases; Dogs; Enzyme-Linked Immunosorbent Assay; Hospitals, Animal; Hospitals, Teaching; Leishmania infantum; Leishmaniasis, Visceral; Sensitivity and Specificity; Serologic Tests; Spain
PubMed: 35181302
DOI: 10.1016/j.actatropica.2022.106371 -
Immunity, Inflammation and Disease Jun 2020In canine visceral leishmaniasis (CVL), lymphopenia, and the disorganization of lymphoid organs such as spleen and lymph nodes have been demonstrated. However, the...
INTRODUCTION
In canine visceral leishmaniasis (CVL), lymphopenia, and the disorganization of lymphoid organs such as spleen and lymph nodes have been demonstrated. However, the involvement of thymus in CVL has not been evaluated so far. Herein, we investigated whether the thymus can be colonized by Leishmania infantum in naturally infected dogs.
METHODS
Thymus were obtained from 16 of 58 dogs and samples of this organ were submitted to immunohistochemistry for laminin and fibronectin detection, histopathology, in situ hybridization and polymerase chain reaction (PCR) targeting the gene ITS-1 for Leishmania and sequenced. Samples of spleen, skin and popliteal lymph nodes were collected and submitted to immunohistochemistry and parasitological culture followed by multilocus enzyme electrophoresis.
RESULTS
L. infantum was identified in all dogs. DNA and amastigote forms of Leishmania were detected in the thymus from 16 dogs by PCR and in eight by immunohistochemistry. Besides thymus, parasites were detected in spleen, lymph nodes, and skin. A granulomatous or pyogranulomatous thymitis was observed in eight dogs associated to intact amastigotes forms of this parasite. Fibronectin deposition in thymus was higher in dogs with more clinical signs.
CONCLUSIONS
These results demonstrate that the thymus of dogs can be parasitized by L. infantum, which may generate inflammatory reactions leading to alterations in thymic microarchitecture.
Topics: Animals; DNA, Protozoan; Dog Diseases; Dogs; Female; Leishmania infantum; Leishmaniasis, Visceral; Lymph Nodes; Male; Parasite Load; Skin; Spleen; Thymus Gland
PubMed: 32207879
DOI: 10.1002/iid3.285 -
Parasites & Vectors Oct 2023Asymptomatic infection is the most common outcome of exposure to Leishmania parasites. In the Mediterranean region, where Leishmania infantum is endemic, studies on the...
BACKGROUND
Asymptomatic infection is the most common outcome of exposure to Leishmania parasites. In the Mediterranean region, where Leishmania infantum is endemic, studies on the prevalence of asymptomatic infection have often relied on serological testing in blood donors. In Spain, regional studies have shown seroprevalence in blood donors between 1 and 8%; in Portugal, values of 0 and 2% were suggested by two localized studies, in different populations. The purpose of this study was (i) to estimate the prevalence of asymptomatic Leishmania infection in blood donors in mainland Portugal, and (ii) to study the association between the detection of antibodies to Leishmania and sociodemographic factors, and also the knowledge, perceptions and practices (KPP) of the blood donors regarding leishmaniasis.
METHODS
A cross-sectional study targeted the population of people who donated blood in mainland Portugal. Participants, distributed proportionally by municipality and aged between 18 and 65 years, were selected randomly in 347 blood collection points between February and June 2022, and completed a sociodemographic and a KPP questionnaire. Detection of anti-Leishmania antibodies in serum was performed using an ELISA commercial kit. Individual KPP scores were calculated by adding grades defined for each question.
RESULTS
Globally, 201/3763 samples were positive. The estimated national true seroprevalence was 4.8% (95% CI 4.1-5.5%). The proportion of positive results was significantly different between NUTS (Nomenclature of Territorial Units for Statistics) regions. Models suggested that seropositivity was significantly higher in male sex, people older than 25 years, or residing in the Centro NUTS2 region, but not in dog owners nor people with lower KPP scores. Overall, 72.3% of participants had previously heard of leishmaniasis and, in multivariate analysis, a higher Knowledge score was associated with age 25-40 years, female sex, ownership of dogs, and higher education.
CONCLUSIONS
Global estimated true seroprevalence (4.8%) was similar to previous regional studies in blood donors in neighboring Spain. Higher seroprevalence values in the NUTS2 Centro region were consistent with incidence data from humans and seroprevalence studies in dogs. On the other hand, the low values in the Alentejo and the high values in the northern subregions may be the result of geographical shifts in parasite circulation due to climate change and should prompt localized and integrated, vector, canine, and human research, following a One Health approach.
Topics: Humans; Male; Animals; Dogs; Female; Adolescent; Young Adult; Adult; Middle Aged; Aged; Portugal; Blood Donors; Asymptomatic Infections; Seroepidemiologic Studies; Prevalence; Cross-Sectional Studies; Dog Diseases; Leishmaniasis; Leishmania infantum; Antibodies, Protozoan; Leishmaniasis, Visceral
PubMed: 37817278
DOI: 10.1186/s13071-023-05980-1 -
Veterinary Medicine and Science Nov 2022In recent years, cases of human visceral leishmaniasis (HVL) have been reported in some districts of Golestan Province, northeastern Iran, particularly in rural areas....
BACKGROUND
In recent years, cases of human visceral leishmaniasis (HVL) have been reported in some districts of Golestan Province, northeastern Iran, particularly in rural areas. Recent epidemiological evidence in Leishmania infantum endemic regions of in Iran indicates approximately 50%-80% of seropositive dogs are asymptomatic for Leishmania infection.
OBJECTIVES
The goal in this study was to determine Leishmania species infecting domestic dogs in Golestan Province, Iran.
METHODS
Between 2015 and 2016, blood samples were obtained from 100 domestic dogs in rural regions of Golestan Province, northeastern Iran. All samples were tested for anti-Leishmania antibodies using a direct agglutination test (DAT), and for Leishmania spp. kinetoplast DNA (kDNA) using PCR.
RESULTS
Seven (7%) dogs were antibody positive and 25 dogs (25%) were Leishmania spp. DNA positives by PCR positive for leishmaniasis. Four of the seven (71%) antibody-positive dogs and 19 of the 25 (76%) PCR-positive dogs were asymptomatic. The rate of infection detected by PCR was significantly higher in male dogs (21/75, 28%) than that in female dogs (4/25, 16%). The ITS1 PCR-RFLP assay identified the presence of L. infantum, L. tropica or Crithidia spp. in the 25 PCR-positive samples.
CONCLUSIONS
The high proportion of asymptomatic dogs in the study areas represent they act as potential reservoirs in the transmission cycle of Leishmania spp. and also Crithidia fasciculata as an emerging agent for the first time. Moreover, our data showed that PCR is a more reliable assay than DAT for detecting Leishmania spp. infection among asymptomatic dogs.
Topics: Humans; Female; Male; Dogs; Animals; Leishmania infantum; Leishmaniasis, Visceral; Leishmania tropica; Crithidia fasciculata; Iran; Dog Diseases
PubMed: 36063538
DOI: 10.1002/vms3.929 -
Parasitology Mar 2022Leishmaniasis is an infectious disease in which different clinical manifestations are classified into three primary forms: visceral, cutaneous and mucocutaneous. These...
Leishmaniasis is an infectious disease in which different clinical manifestations are classified into three primary forms: visceral, cutaneous and mucocutaneous. These disease forms are associated with parasite species of the protozoan genus Leishmania. For instance, Leishmania infantum and Leishmania tropica are typically linked with visceral (VL) and cutaneous (CL) leishmaniasis, respectively; however, these two species can also cause other form to a lesser extent. What is more alarming is this characteristic, which threatens current medical diagnosis and treatment, is started to be acquired by other species. Our purpose was to address this issue; therefore, gel-based and gel-free proteomic analyses were carried out on the species L. infantum to determine the proteins differentiating between the parasites caused VL and CL. In addition, L. tropica parasites representing the typical cases for CL were included. According to our results, electrophoresis gels of parasites caused to VL were distinguishable regarding the repetitive down-regulation on some specific locations. In addition, a distinct spot of an antioxidant enzyme, superoxide dismutase, was shown up only on the gels of CL samples regardless of the species. In the gel-free approach, 37 proteins that were verified with a second database search using a different search engine, were recognized from the comparison between VL and CL samples. Among them, 31 proteins for the CL group and six proteins for the VL group were determined differentially abundant. Two proteins from the gel-based analysis, pyruvate kinase and succinyl-coA:3-ketoacid-coenzyme A transferase analysis were encountered in the protein list of the CL group.
Topics: Animals; Humans; Leishmania infantum; Leishmania tropica; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Parasites; Proteomics
PubMed: 34758895
DOI: 10.1017/S0031182021001967 -
Viruses Aug 2021Sand flies transmit , which is responsible for causing leishmaniasis, as well as many phleboviruses, including the human pathogenic Toscana virus. We screened sand flies...
Sand flies transmit , which is responsible for causing leishmaniasis, as well as many phleboviruses, including the human pathogenic Toscana virus. We screened sand flies collected from a single site between 2017 and 2020 for the presence of both phleboviruses and . The sand flies were sampled with attractive carbon dioxide traps and CDC light traps between May and October. We collected more than 50,000 sand flies; 2826 were identified at the species level as (98%) or (2%). A total of 16,789 sand flies were tested in 355 pools, and phleboviruses were found in 61 pools (6 Toscana virus positive pools, 2 Corfou virus positive pools, 42 Fermo virus positive pools, and 7 Ponticelli virus positive pools, and 4 unidentified phlebovirus positive pools). was found in 75 pools and both microorganisms were detected in 16 pools. We isolated nine phleboviruses from another 2960 sand flies (five Ponticelli viruses and for Fermo viruses), not tested for ; the complete genome of a Fermo virus isolate was sequenced. The simultaneous detection in space and time of the Fermo virus and is evidence that supports the co-circulation of both microorganisms in the same location and partial overlap of their cycles. A detailed characterization of the epidemiology of these microorganisms will support measures to limit their transmission.
Topics: Animals; Humans; Insect Vectors; Italy; Leishmania infantum; Leishmaniasis, Visceral; Phlebotomus; Phlebotomus Fever; Phlebovirus; Phylogeny
PubMed: 34452524
DOI: 10.3390/v13081660 -
Parasites & Vectors Oct 2023Visceral leishmaniosis caused by infection with the zoonotic protozoan Leishmania infantum is a life-threatening disease affecting dogs and humans. The sympatric...
BACKGROUND
Visceral leishmaniosis caused by infection with the zoonotic protozoan Leishmania infantum is a life-threatening disease affecting dogs and humans. The sympatric occurrence of L. infantum and Leishmania tarentolae in an area of southern Italy endemic for canine leishmaniosis, where dogs are also exposed to the latter species, suggests the persistence of herpetophilic L. tarentolae in a non-permissive host, therefore raising questions about the performance of serological diagnostic tests routinely employed.
METHODS
The diagnostic performance of serological tests such as the immunofluorescence antibody test (IFAT), two commercial immunoenzymatic assays (i.e. NovaTec VetLine Leishmania ELISA® and rK39 ICT®) and an in-house enzyme-linked immunosorbent assay (ELISA) was evaluated in healthy dogs seropositive to L. infantum, whereas the only IFAT available was used to detect antibodies to L. tarentolae.
RESULTS
With the IFAT, out of a total of 104 dogs tested, 15 were seronegative for L. infantum of which three were L. tarentolae seropositive' and 89 were L. infantum seropositive. Of the latter 89 dogs, representing the highest proportion of seropositive animals (85.6%) detected by IFAT' 66 were also seropositive for L. tarentolae. Cohen's kappa (κ) agreement coefficient between the IFAT results and those of all the other tests was very low, and the IFAT results were significantly different from those of all the other serological tests as calculated by Cochran's Q-test. Analysis using the Bayesian latent class (Bayes-LCA) showed that the in-house ELISA and IFAT contributed the most towards identifying infected and non-infected dogs, respectively. The IFAT test showed low positive predictive value (59.5%), but high negative predictive value (100%).
CONCLUSIONS
These results demonstrate that the IFAT for L. infantum, although highly sensitive, may not be considered a useful diagnostic test due to its low specificity. Therefore, an accurate serological tool with high specificity is mandatory for avoiding cross-reaction in epidemiological contexts where the two species of Leishmania occur in sympatry.
Topics: Humans; Animals; Dogs; Leishmania infantum; Bayes Theorem; Sympatry; Sensitivity and Specificity; Antibodies, Protozoan; Leishmaniasis, Visceral; Enzyme-Linked Immunosorbent Assay; Serologic Tests; Dog Diseases
PubMed: 37807047
DOI: 10.1186/s13071-023-05981-0 -
Frontiers in Cellular and Infection... 2019B-1 cells are an innate-like population of B lymphocytes that are subdivided into B-1a and B-1b distinguished by the presence or absence of CD5, respectively. B-1 cells... (Review)
Review
B-1 cells are an innate-like population of B lymphocytes that are subdivided into B-1a and B-1b distinguished by the presence or absence of CD5, respectively. B-1 cells can act as regulatory B cells, are able to present antigen and produce IL-10. Leishmaniasis in humans is a complex of diseases caused by parasites of the genus . More than 20 species can infect humans, with each species causing the development of different immunological responses in the host. Susceptibility is usually related to the production of anti-inflammatory cytokines while the production of Th1 cytokines is indicative of resistance. However, few studies have attempted to evaluate the role of B-1 cells during either the infection or interaction with parasites. studies were performed using XID mice model, BALB/Xid mice have a mutation in the Bruton's tyrosine kinase, which is an important enzyme for developing B-1 and maturing B-2 lymphocytes leading to the presence of immature B-2 cells. Here, we compile these studies and assess the influence of B-1 cells on disease progression with different species.
Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; B-Lymphocyte Subsets; B-Lymphocytes; Cytokines; Disease Models, Animal; Disease Progression; Humans; Interleukin-10; Leishmania; Leishmania infantum; Leishmania major; Leishmaniasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Th1 Cells
PubMed: 31993374
DOI: 10.3389/fcimb.2019.00424