Search Results (272)

Background: Leishmaniasis, mainly cutaneous leishmaniasis (CL), is endemic in Israel. In recent years, the diagnosis of leishmaniasis has transitioned to a molecular diagnosis. Objective: To summarize all cases of leishmaniasis and the identified species seen in Israel based on molecular diagnosis. Methods: A retrospective study was performed of patients diagnosed with leishmaniasis between January 2017 and December 2022. All five medical centers in Israel in which Leishmania diagnosis is performed were included: Soroka, HaEmek, Hadassah, Rambam, and Sheba, all utilized molecular diagnostic methods. Data on the annual number of cases, species, age, and gender were retrieved. Results: During the years 2017–2022, a total of 4168 cases of leishmaniasis were diagnosed, which corresponds with ~7/100,000 inhabitants. L. (L.) major and L. (L.) tropica accounted for 84% and 14%, respectively. During the years 2020–2021, L. (L.) infantum emerged as a new form of cutaneous disease [2.7% of cases during this period]. Visceral L. (L.) infantum was found in five cases. Imported New World leishmaniasis accounted for 1% of the cases. L. (L.) major affected more males (67%) while L. (L.) tropica commonly affected more children and caused more facial lesions. Conclusion: The mean annual number of cases during these years is ~700. The dominant species is L. (L.) major. Since 2020, cutaneous L. (L.) infantum is an emerging infection in Israel. Full article

Background: Neglected tropical diseases (NTDs), including leishmaniasis, trypanosomiasis, and schistosomiasis, impose a significant public health burden, especially in developing countries. Despite control efforts, treatment remains challenging due to drug resistance and lack of effective therapies. Objective: This study aimed to synthesize the current research on the combination therapy and phytochemical-loaded nanosystems, which have emerged as promising strategies to enhance treatment efficacy and safety. Methods/Results: In the present review, we conducted a systematic search of the literature and identified several phytochemicals that have been employed in this way, with the notable efficacy of reducing the parasite load in the liver and spleen in cases of visceral leishmaniasis, as well as lesion size in cutaneous leishmaniasis. Furthermore, they have a synergistic effect against Trypanosoma brucei rhodesiense rhodesain; reduce inflammation, parasitic load in the myocardium, cardiac hypertrophy, and IL-15 production in Chagas disease; and affect both mature and immature stages of Schistosoma mansoni, resulting in improved outcomes compared to the administration of phytochemicals alone or with conventional drugs. Moreover, the majority of the combinations studied demonstrated enhanced solubility, efficacy, and selectivity, as well as increased immune response and reduced cytotoxicity. Conclusions: These formulations appear to offer significant therapeutic benefits, although further research is required to validate their clinical efficacy in humans and their potential to improve treatment outcomes in affected populations. Full article

Visceral leishmaniasis (VL) is a neglected tropical disease that is potentially fatal when untreated. Current diagnostic methods have limitations that contribute to ongoing transmission and poor prognosis. Thus, new tests are needed to provide quick, accurate diagnoses and evaluate clinical progression and treatment efficacy. The monokine induced by interferon-gamma (MIG) and interferon-gamma-inducible protein 10 (IP-10) has been associated with the host susceptibility to VL with potential diagnostic and prognostic purposes. We performed a systematic review using four search databases (Scopus, PubMed, Web of Science, and MEDLINE) to identify studies assessing MIG and IP-10 as potential biomarkers in patients with VL across various clinical conditions. A total of 13 studies were potentially eligible and included in this review. The articles, in general, reveal that the chemokines MIG and IP-10 are elevated in response to infection by Leishmania spp., acting on the host’s resistance to the development of the disease. They are associated with asymptomatic conditions and after VL treatment, and this relationship can be observed in both immunocompetent and immunocompromised individuals. Consequently, these chemokines hold relevance in the diagnoses and appropriate management of individuals with VL. Full article

Miltefosine, an orally administered drug, is an important component of the therapeutic arsenal against visceral and mucosal forms of leishmaniasis. However, data regarding the safety and tolerability of miltefosine treatment for cutaneous leishmaniasis (CL) are relatively limited. The aim of this study was to evaluate the tolerability, safety, and adverse events (AEs) of miltefosine treatment in patients with CL. In this cohort study, we reviewed the medical records of all miltefosine-treated patients between 1 January 2016 and 31 December 2022, at Israel Defense Forces military dermatology clinics and the dermatology and Tropical Medicine Clinics at Chaim Sheba Medical Center, Ramat-Gan, Israel. A total of 68 patients (54 males, 79%) with a median age of 30.3 ± 15.6 years (range: 18–88) were included in this study. Leishmania species were identified as L. major (n = 37, 54.4%), L. tropica (n = 12, 17.6%), L. braziliensis (n = 18, 26.5%), and L. infantum (n = 1, 1.5%) using polymerase chain reaction (PCR). Miltefosine tablets were administered orally at a dose of 50 mg, three times daily, for 28 days. Overall, 44 patients (65%) completed the 28-day treatment, and the remaining patients required dose reduction or early discontinuation of treatment. AEs (of any degree) were common, reported in 91% of patients. Both previously reported and previously unreported AEs were documented. Gastrointestinal symptoms (66.1%) and malaise (23.5%) typically occurred during the first two weeks of treatment and tended to subside. Other AEs, including acute renal failure (20.6%), sudden and severe pleuritic chest pain (7.6%), acne exacerbation (11.8%), suppuration of CL lesions (17.8%), and AEs related to the male genitourinary system (39.6% of males), typically occurred towards the end of treatment. The latter included testicular pain, epididymitis, diminution or complete absence of ejaculate, inability to orgasm, and impotence. Severe AEs necessitated treatment discontinuation (29.4%) or hospitalization (10.3%). URTI-like symptoms, arthritis, cutaneous eruption, pruritus, and laboratory abnormalities were also observed. Overall, the cure rate (for all patients combined) evaluated 3 months after the completion of treatment was 60%. The tolerability of miltefosine treatment for CL is low. Close clinical and laboratory monitoring is required during treatment, as severe AEs are not uncommon. As new insights regarding its toxicities emerge, further studies are required to define the role of miltefosine in the treatment of CL. Full article

Human zoonotic visceral leishmaniasis (ZVL) and canine leishmaniasis (CanL) constitute a major public and veterinary health concern and are both caused by the infection with the protozoan parasite Leishmania infantum. One of the main target organs in CanL is the liver. This complex organ, composed of various highly specialized cell types, has garnered significant attention from the scientific community as a crucial player in innate immune functions. In the context of CanL, liver infection by parasites and the host immune response generated strongly influence the disease outcome. Thus, taking advantage of a co-culture system involving canine hepatocytes and L. infantum-infected autologous Kupffer cells (KCs), allowing cell-to-cell interaction, the current report aims to shed light on the hepatocyte-KCs immune interaction. The co-culture of infected KCs with hepatocytes revealed a vital role of these cells in the activation of a local immune response against L. infantum parasites. Although KCs alone can be immunologically silenced by L. infantum infection, the cell-to-cell interaction with hepatocytes in co-culture can lead to local immune activation. In co-culture it was observed gene expression increased the number of innate immune receptors, specifically cell membrane TLR2 and cytoplasmatic NOD1 along with high TNF-α generation. Altogether, these results suggest that the immune response generated in co-culture could induce the recruitment of other circulating cells to contain and contribute to the resolution of the infection in the liver. This work also enhances our understanding of the liver as a vital organ in innate immunity within the context of CanL. Full article

The accurate diagnosis and identification of Leishmania species are crucial for the therapeutic selection and effective treatment of leishmaniasis. This study aims to develop and evaluate the use of high-resolution melting curve analysis (HRM)-PCR for Leishmania species identification causing visceral leishmaniasis (VL), post-kala-azar dermal leishmaniasis (PKDL) and cutaneous leishmaniasis (CL) in the Indian subcontinent. Two multi-copy targets (ITS-1 and 7SL-RNA genes) were selected, and an HRM-PCR assay was established using L. donovani, L. major, and L. tropica standard strain DNA. The assay was applied on 93 clinical samples with confirmed Leishmania infection, including VL (n = 30), PKDL (n = 50), and CL (n = 13) cases. The ITS-1 HRM-PCR assay detected as little as 0.01 pg of template DNA for L. major and up to 0.1 pg for L. donovani and L. tropica. The detection limit for the 7SL-RNA HRM-PCR was 1 pg for L. major and 10 pg for L. donovani and L. tropica. The ITS-1 HRM-PCR identified 68 out of 93 (73.11%) leishmaniasis cases, whereas 7SL-RNA HRM-PCR could only detect 18 out of 93 (19.35%) cases. A significant correlation was observed between the kDNA-based low Ct values and ITS-1 HRM-PCR positivity in the VL (p = 0.007), PKDL (p = 0.0002), and CL (p = 0.03) samples. The ITS-1 HRM-PCR assay could identify Leishmania spp. causing different clinical forms of leishmaniasis in the Indian subcontinent, providing rapid and accurate results that can guide clinical management and treatment decisions. Full article

Leishmania infantum is the vector-borne trypanosomatid parasite causing visceral leishmaniasis in the Mediterranean basin. This neglected tropical disease is treated with a limited number of obsolete drugs that are not exempt from adverse effects and whose overuse has promoted the emergence of resistant pathogens. In the search for novel antitrypanosomatid molecules that help overcome these drawbacks, drug repurposing has emerged as a good strategy. Nitroaromatic compounds have been found in drug discovery campaigns as promising antileishmanial molecules. Fexinidazole (recently introduced for the treatment of stages 1 and 2 of African trypanosomiasis), and pretomanid, which share the nitroimidazole nitroaromatic structure, have provided antileishmanial activity in different studies. In this work, we have tested the in vitro efficacy of these two nitroimidazoles to validate our 384-well high-throughput screening (HTS) platform consisting of L. infantum parasites emitting the near-infrared fluorescent protein (iRFP) as a biomarker of cell viability. These molecules showed good efficacy in both axenic and intramacrophage amastigotes and were poorly cytotoxic in RAW 264.7 and HepG2 cultures. Fexinidazole and pretomanid induced the production of ROS in axenic amastigotes but were not able to inhibit trypanothione reductase (TryR), thus suggesting that these compounds may target thiol metabolism through a different mechanism of action. Full article

Leishmaniasis is a neglected disease with a global spread that affects both domestic and wild animals in addition to people. Leishmania donovani is the suspected anthroponotic cause of visceral leishmaniasis (VL) in India, where it is an endemic disease. The reservoir hosts play a crucial role in the life cycle of the Leishmania parasite. The complicated connection between the pathogen, vector, and reservoir exhibits geographical and temporal diversity. Human-to-human and, to a lesser extent, human-to-animal transmission are the principal mechanisms for the maintenance of anthroponotic diseases. A number of animals were examined for the presence of Leishmania parasites and the findings were reviewed in order to examine the role of animal reservoirs in domestic transmission of cutaneous leishmaniasis in endemic regions of India. The analysis objective was to assess the research conducted on domestic animals’ propensity to spread L. donovani in endemic areas, with a particular emphasis on how proximity and animal density may impact the prevalence of human leishmaniasis. Species of the L. donovani complex have distinct enzootic, zoonotic, and anthroponotic life cycles that depend on the environment. The majority of Leishmania spp. are zoonotic, spreading from non-human mammals to humans. Many nations have leishmaniasis as an endemic disease, and the Indian subcontinent (ISC) has an estimated two to three lakh people who are at risk. This systematic review evaluates the gaps in our understanding of disease transmission that contradict conventional wisdom about the reservoir(s) of visceral leishmaniasis and efforts to manage it on the Indian subcontinent. Fundamental concerns in VL epidemiology and ecology will be clarified by a better understanding of L. donovani infection in domestic animals and its transfer to sandflies. A deliberate, systematic search was conducted on PubMed, Science Direct, and Google Scholar using keywords such as “Leishmania donovani”, “zoonotic visceral leishmaniasis”, and “wild animal reservoir for Leishmania donovani”. A total of 530 potentially relevant references were obtained from these databases, and 507 were not considered due to copy avoidance, irrelevant titles, research publications from nations other than India, or modified compositions. Among the remaining 23 investigations, 20 were rejected, and only 3 were included in the present study. Finally, three research papers with 867 goats, 161 cattle, 106 chickens, 26 sheep, three buffaloes, 406 dogs, and 309 rats were reported. Along with these data, studies across Asian and African countries that are considered VL-endemic areas have been discussed. According to the review, goats are the epidemic’s primary host and possible reservoir in several regions of India. In the endemic regions of the disease, some species of rodents, along with the canines, appear to be maintaining the L. donovani transmission cycle. Full article

Leishmania infantum is considered the predominant Leishmania species responsible for visceral leishmaniasis (VL) in Greece but limited molecular-typing-based studies have been performed so far. We retrospectively analyzed data and serum samples collected from 3661 individuals suspected for VL in a sixteen-year period, from 2005 to 2020, to study the seasonality and demographic characteristics of VL cases and to define the L. infantum genotypes circulating in the country. Serum samples were tested with immunofluorescence assay and/or molecular assay. qPCR Leishmania-positive samples were subjected to genotypic analysis based on polymorphisms in 12 microsatellite regions of the internal transcribed spacers (ITSs) 1 and 2. We diagnosed 219 definite (6%, sample with a positive molecular assay and/or antibody titer ≥ 1:400) and 230 probable (6.3%, sample with antibody titer between 1:100 and 1:200) VL cases. Data analysis revealed that amongst VL-definite cases, the age group (≥65) constitutes the most affected factor, since 36.9% of the VL cases belonged to this age group. Amongst the VL definite cases, the most frequently reported symptoms were fever (83%), splenomegaly (49%), and hepatomegaly (40%), but this was not the case for immunocompromised patients that developed non-typical symptoms of leishmaniasis. Although no statistically significant differences in the overall seasonality of VL cases were observed, February and June showed a significantly higher proportion of VL cases compared to August and December. Genotyping of ITS1 and ITS2 regions revealed that all VL cases belong to ITS type A of L. infantum. Our study provides epidemiological information on VL and demonstrates for the first time, providing genotypic data, the circulation of ITS type A L. infantum in Greece. Full article

Leishmaniasis is an infectious disease caused by protozoa of the genus Leishmania, which is endemic in certain areas of Europe, such as southern Spain. The disease manifests in various clinical phenotypes, including visceral, cutaneous, mucosal, or asymptomatic leishmaniasis. This diversity in clinical outcomes may be influenced by the host immune response, with human leukocyte antigen (HLA) molecules playing a crucial role in determining susceptibility and progression of the infection. This study explores the association between specific HLA variants and Leishmania infantum infection. We recruited four cohorts: a control group, asymptomatic individuals, patients with symptomatic disease, and cohabitants of infected individuals. HLA typing was performed for all participants, followed by an association analysis with infection status and disease progression. Our findings indicate that the HLA-B*38 and HLA-C*03 alleles are associated with protection against L. infantum infection. These results contribute to a better understanding of the disease’s progression, offer potential for new therapeutic approaches such as vaccines, and expand the existing knowledge in the literature. Full article

Phlebotomus argentipes is the predominant sandfly vector of leishmaniasis in the Indian subcontinent. India and Sri Lanka primarily report visceral and cutaneous leishmaniasis caused by Leishmania donovani. We compared Ph. argentipes from two locations, focusing on its morphological, molecular, and salivary protein characteristics. Sandflies were captured using CDC light traps and cattle-baited net traps. Species identification and morphological comparisons were carried out using standard taxonomic keys. DNA extracted from 12 Sri Lankan sandfly samples was PCR-amplified and sequenced for the variable region of Cytochrome oxidase subunit I. Existing DNA sequences of India from GenBank were utilized for a phylogenetic analysis between Sri Lanka and India. Salivary protein profiles were studied using SDS-PAGE, Western blot, and electrospray ionization/LC/MS/MS. The morphological similarities observed between female Ph. argentipes from India and Sri Lanka suggest the presence of Ph. argentipes var. glaucus. A phylogenetic analysis showed genetic divergence between Ph. argentipes populations, but both shared a similar salivary protein profile. A common, strong 30 kDa immunogenic band comprised PagSP05, PagSP06, and PagSP17 proteins of Ph. argentipes. The similarity between the immunogenic salivary proteins suggests their potential use as common markers for vector exposure or immune response stimulants across regions. The use of multiple samples for each category of serum would improve the comprehensiveness of the immunogenic profiles obtained. Full article

The spread of visceral leishmaniasis (VL), a serious global zoonotic parasitic disease, is mostly under control; however, several cases have been reported in recent decades in Xinjiang, China. This study aimed to analyze the epidemiological status and spatiotemporal clustering characteristics of VL in Xinjiang, China, between 2004 and 2021 to provide a basis for the development and implementation of surveillance and response measures. Data on VL incidence during 2004–2021 were collected from the National Diseases Reporting Information System of China. Global spatial autocorrelation analysis, identification of local indicators of spatial association, and spatial–temporal clustering analysis were conducted to identify the distribution and high-risk areas. A total of 2034 VL cases were reported, with a mean annual incidence of 0.50 per 100,000. There was a general decreasing trend in the incidence of VL during our study period. The majority of the cases were reported from October to February of the following year, and fewer cases were reported from April to July. Spatial autocorrelation analysis revealed that the incidence of VL was spatially clustered within a few counties. Significant differences were observed during the study period (Moran’s I = 0.74, Z = 4.900, p < 0.05). The male-to-female ratio was 1.37:1, and most patients were in the age group 0–3 years. Cases were primarily distributed in seven regions and two autonomous prefectures, and Kashgar reported the highest number of cases (1688, 82.98%). Spatial analysis revealed that the aggregation of VL was predominantly observed in southwest Xinjiang. This was in alignment with the high-risk areas identified by spatiotemporal clustering analysis. The H-H clustering region was primarily observed in Gashi, Atushi, Shufu, Injisha, Kashgar, Yepuhu, and Bachu. These findings indicate that integrated control measures must be taken in different endemic areas to strengthen the VL control program in Xinjiang, China. Full article

A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2–5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure–activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC₅₀ = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC₅₀ = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC₅₀ = 3.3 µM, CC₅₀ = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD_7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH_7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold. Full article

Leishmania infantum is the primary cause of visceral and cutaneous leishmaniasis in the European Mediterranean region. Subspecies-level characterization of L. infantum aids epidemiological studies by offering insights into the evolution and geographical distribution of the parasite and reservoir identity. In this study, conducted in north-east Spain, 26 DNA samples of L. infantum were analyzed, comprising 21 from 10 humans and 5 from 5 dogs. Minicircle kinetoplast DNA (kDNA) polymerase chain reaction assays using primers MC1 and MC2, followed by sequencing, were employed to assess intraspecific genetic variability. Single-nucleotide polymorphism (SNP) analysis detected seven genotypes (G1, G2, G12*–G15*, and G17*), with five being reported for the first time (*). The most prevalent was the newly described G13 (54%), while the other currently identified genotypes were predominantly found in single samples. The in silico restriction fragment length polymorphism (RFLP) method revealed five genotypes (B, F, N, P, and W), one of them previously unreported (W). Genotype B was the most prevalent (85%), comprising three SNP genotypes (G1, G2, and G13), whereas the other RFLP genotypes were associated with single SNP genotypes. These kDNA genotyping methods revealed significant intraspecific genetic diversity in L. infantum, demonstrating their suitability for fingerprinting and strain monitoring. Full article

In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficacies in existing treatments and the lack of an efficient vaccine, dog culling is one of the main strategies used to control disease, making the development of new therapeutic interventions mandatory. We previously showed that Tanespimycin (17-AAG), a Hsp90 inhibitor, demonstrated potential for use in leishmaniasis treatment. The present study aimed to test the safety of 17-AAG in dogs by evaluating plasma pharmacokinetics, dose-proportionality, and the tolerability of 17-AAG in response to a dose-escalation protocol and multiple administrations at a single dose in healthy dogs. Two protocols were used: Study A: four dogs received variable intravenous (IV) doses (50, 100, 150, 200, or 250 mg/m²) of 17-AAG or a placebo (n = 4/dose level), using a cross-over design with a 7-day “wash-out” period; Study B: nine dogs received three IV doses of 150 mg/m² of 17-AAG administered at 48 h intervals. 17-AAG concentrations were determined by a validated high-performance liquid chromatographic (HPLC) method: linearity (R² = 0.9964), intra-day precision with a coefficient of variation (CV) ≤ 8%, inter-day precision (CV ≤ 20%), and detection and quantification limits of 12.5 and 25 ng/mL, respectively. In Study A, 17-AAG was generally well tolerated. However, increased levels of liver enzymes–alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)–and bloody diarrhea were observed in all four dogs receiving the highest dosage of 250 mg/m². After single doses of 17-AAG (50–250 mg/m²), maximum plasma concentrations (Cmax) ranged between 1405 ± 686 and 9439 ± 991 ng/mL, and the area under the curve (AUC) plotting plasma concentration against time ranged between 1483 ± 694 and 11,902 ± 1962 AUC 0–8 h μg/mL × h, respectively. Cmax and AUC parameters were dose-proportionate between the 50 and 200 mg/m² doses. Regarding Study B, 17-AAG was found to be well tolerated at multiple doses of 150 mg/m². Increased levels of liver enzymes–ALT (28.57 ± 4.29 to 173.33 ± 49.56 U/L), AST (27.85 ± 3.80 to 248.20 ± 85.80 U/L), and GGT (1.60 ± 0.06 to 12.70 ± 0.50 U/L)–and bloody diarrhea were observed in only 3/9 of these dogs. After the administration of multiple doses, Cmax and AUC 0–48 h were 5254 ± 2784 μg/mL and 6850 ± 469 μg/mL × h in plasma and 736 ± 294 μg/mL and 7382 ± 1357 μg/mL × h in tissue transudate, respectively. In conclusion, our results demonstrate the potential of 17-AAG in the treatment of CVL, using a regimen of three doses at 150 mg/m², since it presents the maintenance of high concentrations in subcutaneous interstitial fluid, low toxicity, and reversible hepatotoxicity. Full article