Cutaneous leishmaniasis (CL) is a parasitic infection that presents a significant public health concern in the Qassim region of Saudi Arabia. This retrospective observational study aimed to investigate the seasonal patterns and distribution of CL cases in the Al-Qassim region, highlighting the importance of these factors in understanding the disease trends. The present study utilized retrospective observational data from a population cohort to examine reported instances of CL over an 8-year period. The Ministry of Health monitored the CL cases from January 2016 to December 2023. The data were systematically arranged by year, gender, age group, nationality, and season to analyze trends and variations in the disease's distribution at the population level. The chi-square test and analysis of variance were used to analyze the data. A total of 1199 confirmed CL cases were reported during the study period, with significant year-to-year variation (p < 0.005). Males accounted for the majority of cases (72.8%), and the highest burden was observed among individuals aged 15-45 years. Saudi nationals represented most reported cases (76.8%). A consistent seasonal pattern was observed, with higher case numbers during spring and winter, while summer showed the lowest incidence. CL in Al-Qassim displays distinct demographic and seasonal trends, particularly among young adult males and during the spring and winter months. These patterns highlight the importance of targeted preventive measures and health interventions in high-risk populations and peak transmission periods.

Environmental drivers and spatio-temporal heterogeneity of Cutaneous Leishmaniasis in Ouarzazate Province, Southeastern Morocco: A 15-year municipal-level analysis (2009-2024).

Host adenosine deaminase reprograms purinergic immunoregulation in Leishmania braziliensis infection.

Ceratopogonid midges of the genus Forcipomyia (subgenus Lasiohelea) are small hematophagous insects widely distributed across tropical regions. In Australia, developmental stages of Leishmania (Mundinia) macropodum have been observed in Forcipomyia (Lasiohelea), suggesting that biting midges may play a role in Leishmania transmission beyond traditional sand fly vectors. However, in Southeast Asia-where leishmaniasis caused by Mundinia species is an emerging autochthonous disease in humans-fundamental information on Forcipomyia (Lasiohelea) diversity and its association with Leishmania remains limited. An integrated morphological-molecular approach was employed to characterize Forcipomyia (Lasiohelea) midges collected using sweep nets from a leishmaniasis-endemic area in Nakhon Si Thammarat Province, Southern Thailand, near the residence of a patient with locally acquired cutaneous leishmaniasis, during January and June 2025. Morphological examination of mandibular dentition, sensory pits, cibarial armature, and spermathecal structure was combined with mitochondrial cox1 barcoding, Bayesian and maximum likelihood phylogenetic analyses, and species delimitation methods (ASAP and mPTP). Because females of the subgenus Lasiohelea possess a single spermatheca, only single-spermatheca females were selected for species identification. Specimens identified as Lasiohelea were subsequently screened for Leishmania using 18S rRNA-qPCR and ITS1-PCR, followed by nanopore-based ITS1 metabarcoding for species-level identification. Vertebrate blood meal sources were also characterized using vertebrate cox1 metabarcoding. From 264 collected midges, 72 female specimens with a single spermatheca were selected for analysis. Integrated morphological and molecular data identified seven Lasiohelea specimens forming four genetic clusters, comprising F. (L.) parvitas (n = 2) and three lineages closely related to F. (L.) peditata (n = 2), F. (L.) humilavolita (n = 2), and F. (L.) taiwana (n = 1). These were clearly separated from non-Lasiohelea taxa, including F. (Euprojoannisia) fuscimana and two unclassified Ceratopogonidae lineages. Phylogenetic and species delimitation analyses revealed cryptic geneticdiversity despite morphological similarity. Leishmania DNA was detected in six of seven Lasiohelea specimens. Nanopore ITS1 metabarcoding identified autochthonous species (L. (Mundinia) martiniquensisandL. (M.) orientalis) and additional Leishmaniaspecies (L. (Leishmania) amazonensisandL. (L.) major), including mixed-species detections in four specimens. A single engorged specimen contained DNA from red junglefowl (Gallus gallus spadiceus). This study provides the first integrated characterization of Forcipomyia (Lasiohelea) diversity and associated Leishmania detection in Southeast Asia. The results identified several putatively distinct specieswithin Lasiohelea and provide evidence of natural exposure of these midges to multiple Leishmania species, suggesting a complex parasite-midge association andparasite co-circulation in the local environment. Although vector competence was not assessed, these findings suggest that Forcipomyia (Lasiohelea) may be involved in the circulation of Leishmania parasites and may represent promising candidates for further investigation of vector competence. Future studies focusing on host associations, parasite development, and experimental transmission are needed to clarify their epidemiological significance.

Virus-like particles expressing the Promastigote surface antigen (PSA) of Leishmania donovani have shown great potential as a vaccine candidate against L. donovani infection. However, their potential as a cross-protective leishmaniasis vaccine candidate has remained unexplored. In this study, we generated the L. donovani PSA-expressing influenza virus-like particle vaccines and evaluated their cross-protective potential against Leishmania amazonensis infection in mice. Virus-like particles expressing the L. donovani PSA on influenza M1 protein (LdPSA-VLP) were self-assembled in insect cells using the baculovirus expression system. To evaluate the efficacy of our LdPSA-VLP vaccine, mice were subcutaneously immunized and then challenged with virulent L. amazonensis. LdPSA-VLP immunization elicited L. amazonensis antigen-specific IgG antibodies. Upon challenge infection with mCherry-expressing L. amazonensis, L. amazonensis-specific antibody-secreting cell responses, germinal center B cell, memory B cell, and CD4+/CD8+ T cell responses were markedly enhanced in immunized mice. Footpad inflammation was significantly inhibited, as indicated by decreased proinflammatory cytokine production. LdPSA-VLP provided cross-protection against L. amazonensis by reducing footpad swelling and parasite burden in the footpads. Our findings indicate that LdPSA-VLPs could serve as promising cross-protective vaccine candidates against cutaneous leishmaniasis.

Dose- and time-dependent dissemination of viable Leishmania amazonensis following experimental footpad infection in mice.

Spatio-temporal modeling of zoonotic cutaneous leishmaniasis (ZCL) in the Algerian steppe: Epidemiological insights and climatic associations.

Cutaneous leishmaniasis promotes skin microbial dysbiosis and exacerbation of local inflammatory responses.

The development of novel ferrocenyl quinoline-benzimidazole molecular hybrids against cutaneous leishmaniasis.

Cutaneous leishmaniasis (CL) is endemic in Khyber Pakhtunkhwa (KP) Province of Pakistan, and exploring its epidemiological status is critical for its control. The current study described the spatial occurrence of CL and its associated risk factors in KP. Records of 5123 confirmed CL patients obtained from 17 district hospitals for the year 2020 revealed that Khyber district hospital had the highest influx of CL patients, followed by North Waziristan and Mardan districts. Additionally, a questionnaire to assess CL risk factors was administered to the heads of 576 randomly selected households across the same 17 districts. Multivariate logistic regression analysis of risk factors showed that education, family size greater than five individuals, information about CL, knowledge of the difference between sand flies and mosquitoes and use of insecticide sprays were risk factors for CL. Adult sand flies were sampled using sticky traps that were placed at variable heights at multiple locations within Mardan and Lower Dir districts. Collections showed that the number captured was maximum at the heights of 30–121 cm above the ground. Risk factors for CL and assessment of specific sand fly nocturnal height activities may assist in developing effective control strategies for CL in the province.

IntroductionMucosal leishmaniasis (ML) is a rare, destructive, and recurrent protozoal infection caused by Leishmania species, most commonly Leishmania braziliensis. ML can develop months to years after initial cutaneous leishmaniasis (CL) and may lead to severe mucosal destruction if untreated.Case PresentationWe present a case of a 48‐year‐old healthy male from Venezuela with prior CL treated with intravenous meglumine antimoniate who subsequently developed progressive nasal symptoms consistent with ML. Initial therapy with oral fluconazole was ineffective, but treatment with miltefosine led to symptom resolution. The patient underwent four‐staged reconstructive surgeries with ENT. Thirty‐eight months later, the patient developed recurrent symptoms, and biopsy confirmed infection with L. braziliensis. He was subsequently treated with intravenous amphotericin B, which led to clinical improvement.DiscussionThis case highlights the relapsing nature of ML, its potential for extensive mucosal damage, and the importance of a structured, long‐term care plan. This case in particular is unique given the extended delay before recurrence following miltefosine therapy. The high recurrence rate of L. braziliensis infections underscores the importance of vigilant long‐term follow‐up and consideration of systemic therapy. Multidisciplinary management is often necessary to optimize outcomes.ConclusionEarly recognition of ML, timely systemic therapy, structured multidisciplinary care, and adherence to a long‐term surveillance plan are critical to prevent mucosal destruction and manage relapses effectively. Extended surveillance may be warranted to detect late relapses in patients treated with newer or more effective agents.

Synergistic anti-leishmanial effects of Rosmarinic acid and Meglumine Antimoniate against Leishmania major: Integrative in silico, in vitro, and immunomodulatory investigations.

Retraction: Effectiveness of carbon dioxide cryotherapy for the treatment of cutaneous leishmaniasis: Systematic review and meta-analysis

Bicyclic Lactams From Chiral Imines: Synthesis, Structural Optimization, and Biological Evaluation of Promising Antileishmanial Agents.

SUMMARYJorge Lobo's disease (JLD) is a chronic cutaneous and subcutaneous mycosis endemic to the Amazon Basin and tropical rainforests of Latin America. Despite more than a century of study, the disease remains underrecognized, poses significant diagnostic challenges, and is often therapeutically refractory. Here, we synthesize historical, clinical, and ecoepidemiological evidence; provide a practical diagnostic approach; and highlight unresolved questions. Clinically, JLD presents as slowly progressive keloid-like nodules and plaques on exposed areas. Diagnosis relies on direct microscopy and histopathology showing chains of thick-walled yeast-like cells connected by narrow-neck budding; culture is not feasible, and molecular assays are rarely available outside reference centers. We contrast JLD with key mimickers (cutaneous leishmaniasis, chromoblastomycosis, leprosy, atypical mycobacterioses, and non-infectious lesions such as keloid scars) and summarize current management options, emphasizing when surgery alone suffices and when prolonged azole therapy should be considered. From an ecoepidemiological perspective, historical settlement patterns, occupational exposures, and environmental disturbance in humid forest biomes appear to have amplified human contact with putative environmental reservoirs. New phylogenomic data position Paracoccidioides lobogeorgii as an early-diverging lineage within Paracoccidioides, refining prior MLST-based inferences. We outline practical surveillance steps to address under-ascertainment, standardized case definitions, sentinel reporting, and laboratory quality assurance and propose research priorities spanning environmental detection, host-pathogen interactions, and therapeutic evaluation. We contextualize the disease within broader frameworks of fungal emergence, structural neglect, and environmental disruption, arguing that revisiting JLD is not merely retrospective but a necessary scientific and ethical priority.

Cutaneous leishmaniasis is a parasitic skin disease for which current treatments often fail, highlighting the need for new therapeutic approaches. While high parasite burdens are associated with delayed healing, excessive protective immune responses, including elevated IFN-γ production, have also been linked to worse clinical outcomes, indicating that immunopathology contributes significantly to disease progression. Acriflavine is an antimicrobial compound with reported anti-leishmanial activity and the ability to inhibit hypoxia-driven responses. Because Leishmania -infected skin is hypoxic in both mice and humans, and hypoxia has been implicated in disease pathogenesis, we investigated whether acriflavine alters the course of cutaneous leishmaniasis by affecting parasite control and/or host immune responses. We found that acriflavine treatment significantly reduced lesion size in Leishmania major -infected mice. Unexpectedly, this improvement occurred without changes in parasite burden. Instead, acriflavine treatment reduced the frequency of dendritic cells within lesions and decreased their expression of MHC class II, which correlated with fewer IFN-γ-producing CD4 T cells at the site of infection. These findings indicate that acriflavine ameliorates disease by limiting dendritic cell activation and subsequent IFN-γ-driven immunopathology rather than enhancing parasite clearance. Together, our results identify acriflavine as a potential host-directed therapeutic strategy for cutaneous leishmaniasis and support targeting hypoxia-associated pathways to reduce tissue damage driven by excessive inflammatory responses.

Dermal sinus tracts (DST) are rare epithelial-lined anomalies, typically located along the midline and diagnosed in early life. Cutaneous leishmaniasis (CL), although endemic in many regions, rarely involves non-exposed sites or congenital structural anomalies. To our knowledge, no prior report has described CL occurring within a latent lateral DST.We present the case of a woman in her mid-50s with a chronic draining gluteal lesion whose induration and dermoscopic features mimicked a keratinising tumour. Her history revealed a previous lesion 20 years earlier, adjacent to the current lesion site and likewise characterised by chronic discharge; it had spontaneously resolved, leaving an atrophic scar. Clinical and parasitological evaluations confirmed CL, while histological examination of the excised specimen demonstrated a chronic fistulous tract, consistent with a dermal sinus tract in the appropriate clinical and surgical context, without granulomas or malignancy. Dermoscopic findings included central erosion, starburst-like structures, polymorphous vessels and white halos, evolving over time despite parasitological cure. Surgical excision revealed a blind-ended, non-communicating sinus tract with chronic inflammatory remodelling.This case illustrates how a dormant congenital anomaly may function as a localised immunocompromised cutaneous district, creating a permissive microenvironment for parasitic colonisation. It also highlights the diagnostic complexity generated by overlapping dermoscopic features. Awareness of such rare presentations is crucial in endemic areas to ensure accurate diagnosis and prompt management.

Interferon-induced transmembrane (IFITM) proteins underpin antiviral responses, yet their role in bacterial infections remains underexplored, particularly for parasites. We probed the role of IFITM1 in Mycobacterium tuberculosis (Mtb), Listeria monocytogenes (Lm), and Leishmania major infection using IFITM1 knockout mice. Notably, IFITM1 was upregulated in murine and human macrophages, as well as in PBMCs during active tuberculosis (TB), subsiding with therapy. IFITM1 also accumulated in the lungs of outbred mice and macaques that progressed to TB. IFITM1-deficient micedisplayed no differences in the acute phase; however, chronic Mtb infection revealed lower bacterial loads, mitigated lung pathology, dampened inflammatory cell recruitment, and decreased cytokines. IFITM1-/- macrophages curbed intracellular H37RV and HN878 growth, skewing proinflammatory cytokine (IL-1α, IL-1β, IL-6, and nitric oxide) production while phagosome maturation and autophagy remained unaffected. Furthermore, HN878-infected IFITM1-/- mice exhibited increased lung cell death by TUNEL staining, driving enhanced mortality. Lm similarly increased IFITM1 expression in macrophages, liver, and spleen. IFITM1-/- mice exhibited reduced early tissue burdens and serum IFN-γ, TNF, and IL-6, yet liver pathology escalated, driving mortality and suggesting dysregulated inflammation. These macrophages also limited intracellular Lm growth, with increased necrosis. By contrast, L. major footpad swelling and parasitic loads remained unaffected in knockout animals. Together, IFITM1 exacerbates TB and listeriosis pathology by calibrating inflammation against bacterial control, but plays no role in cutaneous leishmaniasis. These findings reveal IFITM1-specific contributions to bacterial but not parasitic infections, favoring disease tolerance.

Leishmaniasis is a neglected tropical disease that urgently requires safer and more effective therapeutic strategies. Rhoifolin (RF), a natural flavonoid with anti-inflammatory and antiparasitic potential, has shown promising biological activities against several infectious diseases. In the present study, the antileishmanial effects of free RF and its niosomal formulation (NRF), alone and in combination with meglumine antimoniate (MA), were investigated against Leishmania major. Niosomes were prepared using Span 40, Tween 40, and cholesterol, resulting in high encapsulation efficiency (90.9%) and a sustained drug-release profile. The antileishmanial activity of RF, NRF, MA, and their combinations against promastigotes was evaluated using both MTT and trypan blue exclusion assays, while anti-amastigote activity was assessed in infected macrophages. NRF exhibited greater efficacy than free RF against both promastigote and amastigote forms of L. major. Combination treatments demonstrated additive interactions (combination index ≈ 1.0) and higher selectivity indices, indicating enhanced efficacy and safety. In addition, treatment with RF, NRF, and their combinations significantly increased LDH release and ROS production in infected macrophages compared with untreated controls. Molecular docking analysis revealed a strong binding affinity of RF toward caspase-3. Furthermore, treatment with RF and NRF significantly modulated apoptosis-related mediators, including increased expression of CASP3, CASP8, and Bax, along with reduced Bcl-2 expression. Immunological analyses also demonstrated macrophage polarization toward the M1 phenotype through upregulation of TNF-α, IFN-γ, IL-12, and iNOS/NO, accompanied by downregulation of IL-10, TGF-β, and ARG1. These immunomodulatory and apoptosis-associated effects were more pronounced in the NRF and NRF + MA groups. Overall, our findings suggest that niosomal RF represents a promising lipid-based delivery system for enhancing the antileishmanial efficacy of RF. The NRF + MA combination may provide a potential therapeutic strategy for improving treatment outcomes and reducing the limitations associated with current therapies for cutaneous leishmaniasis.

BackgroundLeishmaniasis is a parasitic disease caused by Leishmania species and transmitted through sand fly bites, affecting some of the most vulnerable populations globally. Current treatments are limited by high toxicity, poor tolerability, and resistance. Plant-based therapies offer a promising alternative, but human evidence has not been comprehensively reviewed. This review summarizes current evidence on the efficacy and safety of plant-based treatments for leishmaniasis in humans.Methodology/findingsWe conducted a systematic review including studies that evaluated the efficacy and safety of plant-based treatments for leishmaniasis in humans. This review was registered with PROSPERO (ID: CRD42024567764). We searched PubMed, Scopus, and Web of Science from inception to May 28, 2024. Risk of bias was assessed using the Cochrane RoB 2 tool. We summarized the main study results qualitatively and quantitatively (where possible) by estimating risk ratios with 95% confidence intervals for treatment outcomes using the meta package in R. Ten studies met the inclusion criteria, nine from Iran and one from Sudan, all focused on cutaneous leishmaniasis (CL). Most used topical creams derived from medicinal plants, either alone or with conventional treatments. In studies combining herbal and standard treatments, four of six studies showed better outcomes in the intervention group. In studies using only the plant-based treatments compared to a standard treatment group, two of four showed better outcomes in the intervention group. Quantitative analysis of eight studies indicated significant healing improvements in the intervention group in three studies, specifically those using Juniperus excelsa, Nigella sativa, and poly-herbal formulations consisting of the pure extract mixture of Althaea (A.) rosa, A. officinalis, and members of the families Leguminosae, Faliaceae, Malvaceae, and Lythraceae (named Z-HE). Mild side effects such as itching and burning were reported with some herbal treatments, while conventional therapies caused more severe reactions in some cases. The risk of bias was mostly high in the studies.ConclusionsThis review highlights the potential of certain plant-based compounds as adjunct or alternative therapies for CL. Despite promising results with Plantago ovata, Juniperus excelsa, and Z-HE poly-herbal extracts, current evidence is limited by methodological weaknesses. Larger, rigorously designed trials with broader representation are needed to confirm efficacy and safety and support policy integration in endemic regions.