Search Results (341)

Leishmaniasis, a neglected tropical disease endemic to 98 countries, affects more than 300 million people worldwide. The disease is transmitted through the bite of infected female phlebotomine sand flies harboring Leishmania parasites. Although infection initiates at the cutaneous inoculation site, Leishmania species exhibit distinct tissue tropisms, resulting in three primary clinical manifestations: cutaneous (CL), mucocutaneous (MCL), and visceral leishmaniasis (VL). The initial stage of infection involves the engulfment of metacyclic promastigotes (MPs) by host phagocytes, a process mediated by early interactions between the MP flagellum and the host cell surface. This study investigates how species-specific MP-flagellar proteomic profiles dictate unique interactions with host cell populations, thereby driving divergent pathogenic outcomes. To address this, we conducted a comparative quantitative proteomic analysis of flagella from Leishmania species representing each clinical form. Our analysis revealed distinct flagellar proteomic signatures that differentiate the VL-causing species, L. infantum, from others. Notably, we identified five virulence factor families that were differentially expressed: amastins, cysteine peptidases, heat shock proteins, promastigote surface antigens, and leishmanolysins. These findings link flagellar surface composition to species-specific pathogenicity, providing molecular insights into early infection dynamics and identifying potential antigenic targets for developing species-specific vaccines and therapeutics. Full article

The Syrian golden hamster (Mesocricetus auratus) is a universally accepted model for visceral leishmaniasis (VL) due to its ability to mimic human disease pathology. Mus musculus (BALB/c) is preferred for evaluating pharmaceutical and immunological responses. This study focuses on the precise role of gene signatures in L. donovani-infected M. auratus and M. musculus, using transcriptomic analysis. Principal component analysis (PCA) revealed distinct clustering among the four groups (uninfected vs. infected spleen samples from M. auratus and M. musculus). After differential expression analysis, 2054 genes in M. auratus and 1108 in M. musculus were found to be differentially expressed, with 153 genes common to both species. Except for 31 genes, most of the commonly dysregulated genes show a similar expression pattern. Although Th1-mediated immune signaling was observed in both cases, the overexpression of LAG3 in both infected groups underscores the important role of T cell exhaustion. Immunological responses against parasite infection in M. auratus appear to be more aggressive, while M. musculus seems more intense. Interestingly, only the M. musculus-infected group shows overexpression of IL-10. Without a definitive role for IL-10, the overexpression of Tgm2, Clec7a, and Adora2b in both species may drive disease outcome. These findings elucidate the immunological mechanisms driving the pathogenesis of VL in rodent models. Full article

Leishmaniases are vector-borne diseases transmitted by phlebotomine sand flies. While bacterial associations in sand fly microbiota are well studied, fungal communities remain poorly characterized, despite their potential role in insect biology and parasite transmission. This study aimed to isolate and characterize yeast-like and filamentous fungi from different developmental stages of Lutzomyia longipalpis, the main vector of visceral leishmaniasis in the Americas, to expand knowledge on fungal microbiota and its possible relevance to vector–parasite interactions. Sand fly eggs, larvae, pupae, and adults were sampled from a laboratory colony. Fungi were isolated from insect tissues and diets using culture-based methods. Morphological identification was complemented by partial sequencing of the ITS1-5.8S-ITS2 rDNA region to identify the species. Four fungi were consistently recovered: Candida guilliermondii, Cutaneotrichosporon dermatis, Penicillium sp., and Aspergillus sp. Their presence varied across developmental stages. Presence in the gut was observed for Cu. dermatis, Penicillium sp. and Aspergillus sp. in larvae and C. guilliermondii in adult females. Evidence suggested their presence in different stages from larvae to pupae, and sex-specific differences in adults, with fungi detected only in females. This work documented the mycobiota that may be associated with L. longipalpis, including the first report of Cutaneotrichosporon in sand flies. These findings highlight fungi that may be potential modulators of sand fly biology and Leishmania development, warranting further investigation into their ecological and epidemiological roles. Full article

Leishmaniasis causes skin ulcers to complex visceral involvement, and available treatment options for humans are highly toxic and have prolonged application schemes. So far, there are no licensed vaccines for humans, so it is necessary to develop a strategy that can prevent the development of the disease. A cellular immune response of a CD4⁺ Th1 profile is essential to eliminate intracellular Leishmania amastigotes; therefore, the identification of sequences that bind to HLA class II pockets could induce a protective immune response. This study aimed to identify CD4⁺ T epitopes from immunogenic Leishmania proteins. First, three prediction tools were used to compare 15-mer sequences throughout the complete protein sequence against 25 HLA-DR alleles using NH, SMT, CPA, CPB, and CPC proteins. Six peptides were identified as strong HLA-DR binders using the three bioinformatic prediction tools. After alignment, molecular docking analysis, and molecular dynamics, the stability and affinity of the peptide–DR4 complex were confirmed for three sequences. This bioinformatics strategy allowed a sequential screening from 1857 to three promising candidates, namely, SMT_133-148, CPA_39-54, and CPA_301-316, which increases the probability of being natural Leishmania spp. CD4⁺ T cell epitopes in humans. Full article

Background/Objectives: Protozoan parasites of the genus Leishmania are causative agents of a group of devastating human diseases, known as leishmaniasis. These microorganisms possess very unusual mechanisms of gene expression that are poorly understood. This study was aimed at analyzing the tRNA repertoire encoded in the Leishmania infantum genome, a species responsible for the most severe form of disease, visceral leishmaniasis. tRNAs are adaptor molecules aimed at decoding mRNAs into proteins. Results: A total of 92 tRNA genes, dispersed on 38 loci, were identified, often located in regions where unidirectional gene arrays converge. Putative intronic sequences were inferred for three tRNA genes, and, remarkably, nine tRNAs were found to overlap with the protein-coding sequences of annotated genes. According to structural predictions, the L. infantum tRNA repertoire covers 49 out of the 61 possible anticodons, but because of the well-documented wobble phenomenon, these are enough to decode all codons in the 8532 protein-coding genes currently annotated in its genome. As illustrated in this study, codon usage is a well-conserved trait among different Leishmania species but it differs substantially regarding its human host. Finally, we analyzed tRNA adaptation index (tAI) parameters, codon usage metrics, and relative protein expression levels. Conclusions: Apart from providing the tRNA gene repertoire and its genome distribution, we have shown the existence of a statistically significant, positive correlation between the tAI scores and protein expression levels in L. infantum promastigotes. Full article

Visceral leishmaniasis (VL) is a rare but increasingly recognized parasitic infection in non-endemic European regions, including Romania. We report two cases of VL diagnosed in Timiș County, Western Romania, in 2020: a 57-year-old male presenting with fever, massive splenomegaly, and severe pancytopenia, and a 51-year-old male presenting atypically with fatigue, bicytopenia, and absence of organomegaly. Both patients were diagnosed through bone marrow aspirate examination revealing Leishmania amastigotes. Both cases were classified as imported VL, with exposure linked to endemic regions of eastern Spain (Castellón and València). These cases highlight the importance of maintaining a high index of clinical suspicion for VL in patients presenting with unexplained cytopenias and elevated inflammatory markers, even in the absence of classic features such as hepatosplenomegaly. The present report underscores the relevance of travel history in non-endemic regions such as Romania and the need for clinical awareness of imported VL in patients returning from endemic areas of southern Europe. Full article

Background: Large language models (LLMs) are increasingly considered as adjuncts for differential diagnostic reasoning, yet their sensitivity to gender-attributed cues in the persona prompt—particularly for neglected tropical diseases (NTDs) and in non-English clinical settings—remains poorly characterised. Objective: The objective of this study was to compare the diagnostic accuracy of one proprietary and three open-weight LLMs for Chagas disease (CD) and visceral leishmaniasis (VL) under paired persona-prompt conditions in which the only manipulated variable was the linguistic gender of the simulated medical persona. Methods: This experimental, paired study evaluated ChatGPT-4o, LLaMA 3 70B, Meditron-70B, and Mixtral 8x7B across 12 cases per disease (n = 24) from real records at a Brazilian teaching hospital. The primary outcome was top-five diagnostic accuracy. A committee of five infectious-disease specialists assessed the biological plausibility of all differentials. Paired comparisons used Wilcoxon signed-rank tests; 95% confidence intervals were calculated using the Wilson-score method. Results: ChatGPT-4o achieved the highest accuracy (CD: 100% under both prompts; VL: 83.3–91.7%). LLaMA 3 70B and Mixtral 8x7B showed moderate performance (41.7–83.3%); the medically fine-tuned Meditron-70B exhibited paradoxically poor accuracy (16.7–25.0%) and the lowest committee-rated plausibility scores. A consistent small numerical trend favoured the female prompt across most model–disease combinations (differences of 0–16.7 percentage points), but no comparison reached statistical significance (all p > 0.05). Conclusions: Gender-attributed persona-prompt variation did not produce a systematic effect on LLM diagnostic accuracy for CD or VL. ChatGPT-4o outperformed the three evaluated open-weight alternatives, and medical-domain fine-tuning did not confer the expected advantage. Expert-validated assessment of hypothesis plausibility should complement target-disease accuracy in clinical LLM evaluation studies, particularly for NTDs. Full article

Background: Human visceral leishmaniasis remains a serious public health problem in Brazil, especially in the Northeast, where transmission persists in various vulnerable settings. Objective: This study aimed to assess temporal trends in the incidence of human visceral leishmaniasis in Maranhão, northeastern Brazil, with emphasis on social vulnerability and regional heterogeneity. Methods: We conducted an ecological, population-based study using confirmed cases of human visceral leishmaniasis reported in Maranhão from 2007 to 2024. Case data were obtained from the Brazilian Notifiable Diseases Information System, and population denominators were derived from national census counts and annual population estimates. Temporal trends in incidence rates were analyzed using joinpoint regression models, stratified by sex, age group, Social Vulnerability Index, and Health Regions. Results: A total of 7830 new cases of human visceral leishmaniasis were reported during the study period. Incidence showed a significant upward trend from 2007 to 2017, followed by a marked decline from 2018 to 2024. A heterogeneous pattern was observed in the average incidence rate of human visceral leishmaniasis across municipalities’ vulnerability categories, as measured by each subindex of the Social Vulnerability Index. Substantial regional heterogeneity was identified, with marked reductions in incidence in the Health Regions of Caxias, Timon, Barra do Corda, and Codó, whereas Santa Inês and Viana showed increasing trends. Conclusions: Despite the decline in incidence, human visceral leishmaniasis remains unevenly distributed throughout Maranhão. These findings underscore the need for geographically targeted interventions and the expansion of public health strategies aimed at preventing and controlling the disease. Full article

Objectives: Visceral leishmaniasis (VL), caused by Leishmania donovani and Leishmania infantum, is a life-threatening neglected tropical disease, particularly in endemic regions such as Djibouti. Current therapies are constrained by toxicity, high cost, and limited availability, highlighting the urgent need for safe, effective, and affordable alternatives. This study aimed to identify novel antileishmanial candidates from Djiboutian medicinal plants using an integrated in silico approach. Methods: A total of 136 phytoconstituents isolated from local medicinal plants were screened via molecular docking against validated protein targets (6UAK and 2JK6). Promising candidates were further analyzed for interaction patterns, drug-likeness according to Lipinski’s Rule of Five, and ADMET properties. Molecular dynamics (MD) simulations over 100 ns were performed to assess the structural stability of selected protein–ligand complexes. Results: Compound C41 emerged as a leading candidate, showing binding affinities of −8.3 kcal/mol and −7.5 kcal/mol toward 6UAK and 2JK6, respectively, comparable to reference drugs. Interaction analysis revealed stable hydrogen bonds and hydrophobic contacts within the catalytic sites. Drug-likeness assessment confirmed compliance with Lipinski’s Rule, while ADMET predictions indicated high intestinal absorption and favorable safety profiles for several candidates. MD simulations corroborated the structural stability of the 2JK6-C41 complex throughout the 100 ns trajectory. Conclusions: These findings underscore Djiboutian medicinal plants as a valuable source of potential antileishmanial leads. Among them, Compound C41 represents a promising candidate for future experimental validation, supporting the development of innovative, safe, and cost-effective therapies against visceral leishmaniasis. Full article

Background/Objectives: Leishmaniasis is a group of diseases caused by obligate intracellular parasites of the Leishmania genus and is classified by the World Health Organization as a category I neglected tropical disease. Leishmania infantum predominantly affects children under five years of age and shows an increasing incidence of cutaneous and visceral forms. The development of new therapeutic alternatives remains challenging, making in silico approaches valuable for accelerating antileishmanial drug discovery. This study aimed to identify new compounds with potential activity against Leishmania infantum amastigotes using artificial intelligence-based classification models. Methods: A curated database of compounds with reported biological activity was constructed. Molecular representation employed zero- to two-dimensional descriptors calculated with Dragon software (v 7.0.10). Unsupervised k-means cluster analysis was applied to define training and external prediction sets. Supervised models were developed on the WEKA platform using IBk, J48, multilayer perceptron, and sequential minimal optimization algorithms. Model performance was assessed through internal cross-validation and external validation procedures. Results: All models achieved classification accuracies above eighty percent for both training and prediction sets, indicating consistent predictive performance and good generalization ability. The validated models were applied to virtual screening of the DrugBank database and a collection of synthetic compounds. This screening campaign enabled the identification of one hundred twenty compounds with potential activity against the amastigote form of Leishmania infantum. Conclusions: Artificial intelligence-based QSAR models proved to be useful tools for prioritizing antileishmanial candidates. The integration of molecular descriptors, machine learning, and virtual screening offers an efficient strategy for drug discovery. Full article

Cutaneous leishmaniasis (CL) caused by Leishmania major is a zoonotic disease transmitted by phlebotomine sand flies. Identification of reservoir hosts is critical for understanding transmission and guiding control. While Psammomys obesus and Meriones shawi are recognized reservoirs in North Africa, the role of other rodents remains unclear. We experimentally assessed the reservoir potential of Acomys cahirinus seurati from southeastern Algeria. Animals were intradermally infected, and clinical signs and infectiousness to sand flies were monitored. Parasite persistence in skin and visceral tissues was measured by quantitative PCR. All animals developed localized, self-limiting lesions. Seven of sixteen individuals transmitted parasites to Phlebotomus papatasi between 10 and 25 weeks post-infection. Parasites were mostly restricted to the inoculation site, with limited dissemination to contralateral pinnae and hindpaws, and rare presence in spleen or liver. Notably, some animals were infectious without visible lesions, indicating that ulceration is not required for transmission. These findings show that A. cahirinus seurati can maintain L. major infection for up to 6 months and transmit parasites to sand flies, fulfilling key criteria of a reservoir host. Thus, this species may contribute to CL transmission in endemic foci lacking classical reservoirs, emphasizing the need to consider alternative rodent hosts in surveillance and control programs in North Africa. Full article

Background: Visceral leishmaniasis (VL) is a life-threatening protozoan disease prevalent in tropical and subtropical regions and a frequent coinfection among people living with HIV. Early identification of patients at high risk of death may reduce case-fatality. This study evaluated the post-test prognostic value of C-reactive protein (CRP) and interleukin-6 (IL-6) as biomarkers of mortality in VL. Methods: A retrospective hospital-based cohort of 101 VL patients was analyzed. CRP and IL-6 concentrations at admission were correlated with clinical findings, the Kala-Cal^® prognostic score, and in-hospital mortality. Results: Eight patients died, most presenting with hemorrhagic manifestations. At admission, 87.1% of patients had both biomarkers above the predefined cut-offs. CRP and IL-6 levels were markedly elevated in patients with hemorrhage or fatal outcomes. The AUC was 0.85 for CRP and 0.87 for IL-6, with no significant difference between markers. Optimal prognostic cut-offs were 150 mg/L for CRP and 90 pg/mL for IL-6. Conclusions: In this sample, CRP and IL-6 showed good prognostic performance in VL. In patients with low initial clinical risk, positive biomarker results substantially increased the probability of death. When combined with Kala-Cal^®, these markers may improve risk stratification and guide referral decisions. Full article

Canine leishmaniasis (CanL) is a major vector-borne disease with zoonotic potential, and oxidative stress plays an important role in its pathogenesis. CanL is a chronic, progressive disease in which clinical signs may develop gradually over months or even years, depending on host immune response and parasite burden. This study aimed to evaluate oxidative DNA damage in dogs with CanL by measuring urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels and oxidative stress markers. A total of 54 dogs, including 34 dogs with CanL and 20 healthy controls, were included. Urinary 8-OHdG and serum malondialdehyde (MDA) were measured using ELISA method, whereas serum TAC and TOC were determined using automated colorimetric method. Dogs with CanL showed significantly higher TAC (1.30 ± 0.05 vs. 1.04 ± 0.06 mmol/L, p = 0.001) and TOC levels (18.91 ± 3.29 vs. 8.23 ± 1.61 μmol H₂O₂ Eq/L, p = 0.002) compared with healthy controls. Although urinary 8-OHdG and MDA levels were higher in infected dogs, these differences were not statistically significant (p > 0.05). These findings indicate a disturbance in oxidative balance in dogs with CanL, characterized by simultaneous increases in both oxidant and antioxidant parameters, while urinary 8-OHdG, as measured by ELISA, may have limited ability to reflect cellular oxidative DNA damage in dogs with CanL, rather than indicating an absence of DNA damage. Full article

Visceral leishmaniasis (VL) is a zoonosis of major public health importance. In urban areas, Lutzomyia longipalpis is the primary vector of Leishmania (L.) infantum. This study assessed the seasonality, spatiotemporal distribution, and climatic factors associated with L. longipalpis abundance in Araçatuba, São Paulo State, and detected Leishmania spp. DNA in captured females. Monthly collections were conducted from March 2023 to February 2024 in 72 households across eight urban areas using CDC-type light traps placed indoors and in peridomestic environments. A total of 1641 specimens (1516 males and 125 females) were captured, with 92.4% originating from peridomestic areas. Area 3 had the highest density (n = 671) and was the only area with PCR-positive females (n = 3). Vector activity peaked in December 2023 (n = 335). Male abundance differed significantly among peridomestic areas, particularly between Areas 3, 5, 6, and 7. In peridomestic areas, higher final temperatures increased vector abundance, whereas higher initial temperatures and humidity reduced it. Indoors, final temperature, humidity, and month were significant predictors. L. longipalpis exhibited a defined seasonal and spatial pattern influenced by climatic conditions. The detection of PCR-positive females (Area 3) highlights the epidemiological role of the vector and underscores the need for targeted interventions to control VL. Full article

Canine visceral leishmaniasis (CVL), caused by Leishmania infantum, is a multisystemic disease in which ocular involvement is frequent but often underestimated. This study aimed to comprehensively evaluate the clinical, ophthalmological, parasitological, hematological, biochemical, and histopathological alterations in dogs naturally infected with L. infantum from an endemic area of northeastern Brazil, with special emphasis on the relationship between ocular manifestations and systemic disease. Twenty-five symptomatic dogs were evaluated through clinical and ophthalmological examinations, parasitological culture, PCR, laboratory analyses, and histopathology of ocular and periocular tissues. Ocular alterations were observed in 80% of the animals, predominantly bilateral and frequently associated with multiple concurrent lesions, including ocular discharge, conjunctivitis, blepharitis, uveitis, and corneal opacity. Functional ophthalmological tests revealed keratoconjunctivitis sicca and corneal ulcers in a substantial proportion of dogs. Hematological abnormalities were highly prevalent, particularly anemia and thrombocytopenia. Comparative analysis demonstrated that dogs with ocular involvement exhibited significantly higher leukocyte counts and segmented neutrophils, as well as increased AST levels, indicating an enhanced systemic inflammatory response. Histopathological examination revealed intense plasmacytic inflammatory infiltrates and the presence of amastigote forms in ocular and periocular tissues, indicating that both immune-mediated and parasite-driven mechanisms could be involved in disease pathogenesis. Collectively, these findings underscore ocular involvement as a clinically relevant manifestation of CVL and reinforce the importance of routine ophthalmological evaluation in clinical management. Full article