Search Results (291)

Proteinopathies, characterized by the misfolding, aggregation, and deposition of proteins, are hallmarks of various neurodegenerative and systemic diseases. Increasingly, research has highlighted the role of protein misfolding in parasitic infections, unveiling intricate interactions between host and parasite that exacerbate disease pathology and contribute to chronic outcomes. The life cycles of parasitic protozoa, including Plasmodium, Toxoplasmosis, and Leishmania species, are complicated and involve frequent changes between host and vector environments. Their proteomes are severely stressed during these transitions, which calls for highly specialized protein quality control systems. In order to survive harsh intracellular conditions during infection, these parasites have been demonstrated to display unique adaptations in the unfolded protein response, a crucial pathway controlling endoplasmic reticulum stress. In addition to improving parasite survival, these adaptations affect host cell signaling and metabolism, which may jeopardize cellular homeostasis. By causing oxidative stress, persistent inflammation, and disturbance of cellular proteostasis, host–parasite interactions also contribute to proteinopathy. For instance, Plasmodium falciparum disrupts normal protein homeostasis and encourages the accumulation of misfolded proteins by influencing host redox systems involved in protein folding. In addition to interfering with host chaperone systems, the parasitic secretion of effector proteins exacerbates protein misfolding and aggregate formation. Autophagy, apoptosis regulation, organelle integrity, and other vital cellular processes are all disrupted by these pathological protein aggregates. Long-term misfolding and aggregation can cause irreversible tissue damage, which can worsen the clinical course of illnesses like visceral leishmaniasis, cerebral malaria, and toxoplasmosis. Treating parasite-induced proteinopathies is a potentially fruitful area of therapy. According to recent research, autophagy modulators, proteasome enhancers, and small-molecule chaperones may be repurposed to lessen these effects. Pharmacological agents that target the UPR, for example, have demonstrated the ability to decrease parasite survival while also reestablishing host protein homeostasis. Targeting the proteins secreted by parasites that disrupt host proteostasis may also offer a novel way to stop tissue damage caused by proteinopathies. In conclusion, the intersection of protein misfolding and parasitic infections represents a rapidly advancing field of research. Dissecting the molecular pathways underpinning these processes offers unprecedented opportunities for developing innovative therapies. These insights could not only transform the management of parasitic diseases but also contribute to a broader understanding of proteinopathies in infectious and non-infectious diseases alike. Full article

Background/Objectives: Malnutrition and visceral leishmaniasis are major public health problems that are responsible for millions of deaths across many countries. Leishmaniasis development and progression are associated with the host immune status. In this context, malnutrition can directly affect the course of leishmaniasis, impairing several components of the immune system. Moreover, malnutrition directly interferes with the tropism of Leishmania in organs, affecting host susceptibility. Therefore, this work aimed to evaluate the influence of nutritional status on the establishment, progression, and treatment of Leishmania infantum infection in malnourished and refed mice. Methods: BALB/c mice were fed either a control or restricted diet, infected with L. infantum promastigotes, and treated with meglumine antimoniate, the standard drug for treating visceral leishmaniasis. The effects of infection were evaluated through limiting dilution analysis (LDA). Results: Compared with control mice, malnourished and refed mice presented a lower parasitic load in the spleen, which correlated with spleen atrophy, and the refeeding process partially reversed but did not fully rescue the infection status. Both groups presented a high parasitic load in the liver. Marasmic malnutrition appeared to impair the efficacy of leishmaniasis treatment; however, the refed groups exhibited a robust decrease in the parasite load, which was comparable to that in the control group subjected to treatment. Conclusions: Our data suggested that marasmic malnutrition affects the establishment and progression of Leishmania infection, in addition to reducing the efficacy of standard treatment. Furthermore, the refeeding intervention used did not fully reverse the observed effects. These findings highlight the potential importance of nutritional interventions in the clinical management of visceral leishmaniasis in malnourished populations. Full article

Leishmania is a protozoan parasite causing a spectrum of pathologies in humans grouped under the name leishmaniasis. Clinical outcomes range from the self-healing cutaneous form to the visceral one that is fatal in the absence of treatment. The leishmaniases are endemic in 98 countries in the tropics, subtropics, and Southern Europe, where 3 million new cases and more than 50,000 deaths are recorded yearly. Control of this disease is challenging as there is no approved vaccine coupled with toxic chemotherapeutics and the development of parasite resistance to some available drugs. It is, therefore, evident that the identification of new control methods, including new therapeutics, should be strongly encouraged. In the present study, thiol organic compounds were synthesized and tested for their activity against Leishmania major, the causative agent of human cutaneous leishmaniasis. Of the 21 compounds tested, 13 were active against L. major promastigotes in vitro at 100 μg/mL. Selected compounds tested in a dose-response assay showed activity at concentration as low as 25 μg/mL, a level of activity similar to that of Amphotericin B, a drug of choice for the treatment of human leishmaniasis. Structure–activity analysis shows that the addition of certain substituents, such as a methoxy group, to a compound that is biologically active renders it inactive. Together, our data demonstrate that functionalized thiols have an in vivo anti-Leishmania activity that is directly linked to their chemical structure. Full article

Leishmania (Leishmania) infantum chagasi infections range from asymptomatic (AS) to severe visceral leishmaniasis (VL). One of the manifestations is an atypical non-ulcerated cutaneous leishmaniasis (NUCL), which occurs in some locations of Central America with few cases of VL. We conducted a transcriptomic analysis of cell-mediated immunity (CMI) on blood samples from NUCL, AS, VL patients from Amapala, Honduras, and healthy controls. RNA-seq revealed a similar perturbation of gene expression in NUCL and AS. Eight gene signatures of CMI were found in NUCL involved in CD8⁺ T lymphocyte infiltration, reactive oxygen species generation, PD-1 receptor ligand, inflammasome assembly, chemotaxis, complement receptor and suppressor immune cell infiltration. NUCL was distinguished from VL by its up-regulation of differently expressed genes (DEGs) related to T lymphocyte exhaustion, adhesion and transmigration of leukocytes, and down-regulation of oxidative stress genes. In contrast, VL exhibited up-regulated DEGs involved in antigen cross-presentation, and similar to VL from Brazil, down-regulated DEGs involved in innate immunity. Corroborating the transcriptome findings, both the Leishmanin skin test, and the immunopathology of NUCL skin lesion defined NUCL as a proinflammatory condition, intermediate between the AS and VL clinical outcomes. That condition may be the underlying element for the benign nature of the NUCL. Full article

Visceral leishmaniasis is a rare parasitic infection in non-endemic regions such as Romania. We report the case of a 25-year-old female kidney transplant recipient from Cluj County, Romania, who developed persistent bicytopenia with anemia and thrombocytopenia. Despite no history of travel outside Cluj County and being the only organ recipient from the same donor to experience signs and symptoms, she was diagnosed with visceral leishmaniasis. The second bone marrow aspirate performed revealed Leishmania amastigotes. She was quickly sent to Victor Babes Infectious Disease Hospital in Bucharest for additional tests and treatment. The kidney function of the patient was maintained. This case highlights the importance of considering leishmaniasis in immunosuppressed patients presenting with unexplained cytopenia, even in non-endemic regions. This is the first documented case of visceral leishmaniasis in a kidney transplant recipient in Romania. The present report could serve as a foundation for future educational programs targeted toward informing both healthcare providers and patients about the risks, diagnosis, and management of leishmaniasis in immunosuppressed individuals in non-endemic regions. Full article

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is fatal if left untreated in over 95% of cases. Leishmaniasis is one of the neglected tropical diseases that tend to thrive in developing regions of the world where inadequate access to healthcare makes it difficult for some people to even receive a diagnosis. This study examined the usefulness of oral swabs as specimens for VL diagnosis, by detecting Leishmania donovani DNA in oral swabs from both VL patients and L. donovani-infected mice. Eighty oral swab (OS) and blood buffy coat (BC) samples were collected from suspected VL cases in Bangladesh. These samples were evaluated using Leishmania kinetoplast minicircle DNA (kDNA) in real-time PCR, and the results showed that 62.5% (50/80) and 67.5% (54/80) of the cases tested positive for the BC specimen and OS, respectively. The OS positivity was statistically comparable to the BC. L. donovani DNA was also detected in an oral swab of all infected BALB/c mice by conventional PCR targeting the large subunit ribosomal RNA gene (LSUrRNA), while it was negative in uninfected mice. This study highlights the potential of practical methods for the molecular diagnosis of VL using oral swabs as a non-invasive, simple, and accurate approach. Full article

Leishmaniasis is a neglected tropical disease caused by a protozoan of the genus Leishmania, which has visceral and cutaneous forms. The symptoms of leishmaniasis include high fever and weakness, and the cutaneous infection also causes lesions under the skin. The drugs used to treat leishmaniasis have become less effective due to the resistance mechanisms of the protozoa. In addition, the current compounds have low selectivity for the pathogen, leading to various side effects, which results in lower adherence to treatment. Various strategies were developed to solve this problem. The bioconjugation between natural compounds with antimicrobial activity and cell-penetrating peptides could alleviate the resistance and toxicity of current treatments. This work aims to conjugate the cell penetration peptide TAT to the guanidine GVL1. The GVL1-TAT bioconjugate exhibited leishmanicidal activity against Leishmania amazonensis and Leishmania infantum with a high selectivity index. In addition, the bioconjugate was more active against the intracellular enzyme CPP than the individual compounds. This target is very important for the viability and virulence of the parasite within the host cell. Docking studies confirmed the higher interaction of the conjugate with CPP and suggested that other proteins, such as trypanothione reductase, could be targeted. Thus, the data indicated that guanidines conjugated with cell-penetrating peptides could be a good approach for developing antileishmanial molecules. Full article

Zoonotic visceral leishmaniasis is caused by Leishmania (Leishmania) infantum and dogs are the main domestic reservoir. This study compared the performance of parasitological tests using semi-automatic needle puncture (SANP) for collecting popliteal lymph node samples with samples collected from the same lymph node by fine needle aspiration puncture (FNAP) and by necropsy for the diagnosis of canine visceral leishmaniasis (CVL). Popliteal lymph node samples were collected from 30 CVL-seropositive dogs from an endemic region in Brazil. After clinical examination and euthanasia, samples were collected from the same lymph node by SANP, FNAP, and necropsy. The reference tests were culture, immunohistochemistry, and histopathology. Positivity for Leishmania spp. was 70% for immunohistochemistry and 33.3% for histopathology. Culture positivity using the different sampling techniques was 77% for necropsy (87% in the first week), 73% for FNAP (82% in the first week), and 63% for SANP (95% in the first week). The combination of SANP and culture proved to be an alternative for the diagnosis of Leishmania spp. in the lymph node samples of dogs because of its high positivity rate and because it is more practical and faster and has a shorter time to positivity by culture when compared to FNAP and necropsy sampling. Full article

The urbanization process has led to significant changes in the landscape, shifting the epidemiological profile of the visceral leishmaniasis (VL) in Brazil. Dogs are considered the main urban reservoir of VL, whose infections precede cases in humans. In order to understand the socio-environmental determinants associated with canine visceral leishmaniasis (CVL), we conducted a spatial analysis of CVL cases in northeastern Brazil from 2013 to 2015, georeferencing 3288 domiciled dogs. We used linear mixed models to understand the ecoepidemiological determinants of CVL spatial relative risk (CVL SRR). Our findings indicate heterogeneity in CVL distribution, with 1 km diameter clusters potentially connected within an estimated 4.9 km diameter by the Ripley-K statistic. In our best-fit model, the CVL SRR was positively correlated with the proportion of households with literate heads, with trees, and with open sewage, but negatively correlated with vegetation phenology and mean income of the census sector. Here, we discuss the potential maintenance source of urban CVL clusters on a One Health framework. These findings highlight the complex interplay of socioeconomic and environmental factors in shaping the spatial distribution of CVL. Full article

Background/Objective: Leishmaniasis is the second deadliest parasitic disease in the world, after malaria, with an estimated 1.6 million new cases each year. While cutaneous leishmaniasis can result in permanent scars from lesions after treatment, the mucocutaneous and visceral diseases can result in life-altering and life-threatening complications. Accurate species diagnosis is critical for treatment and follow-up, and while PCR-based diagnostics can provide sensitive parasite detection and species identification, they are slow, expensive, and not suitable for low-resource settings. In this publication, we describe our efforts to develop a simple, affordable, and instrument-free Leishmania DNA diagnostic that can be used in both high-tech settings and the field. Methods: Computational biology was utilized to design region-targeted RPA oligos and the corresponding CRISPR guides for the detection of all Leishmania species as well as the specific identification of L. (V.) panamensis as a predictor of mucocutaneous disease. Then, we executed systematic approaches for parasite lysis, RPA amplification of DNA, and fluorescent CRISPR crRNA detection. Results: We have demonstrated the ability to detect single-digit parasites without compromising the specificity in identifying single species as the proof of concept for a point-of-care diagnostic. Individual assays were carried out in succession, culminating in an unquenched fluorescent signal quantifiable over negative control. Conclusions: The described work is the foundation which will be implemented into a three-track [all Leishmania, mucocutaneous or visceral only, and a human positive control] assay that we plan to utilize in a Funnel Adapted Sensing Tube (FAST) single use, instrument-free, and affordable diagnostic. Full article

Phlebotomus sichuanensis, considered a potential vector for visceral leishmaniasis (VL), is distributed in the southern Gansu and northern Sichuan regions in China. However, the high similarity in the morphology of P. sichuanensis and P. chinensis s.s. poses unresolved taxonomic challenges. In this study, phlebotomine sand flies were collected from three locations in the southern Gansu and northern Sichuan regions (SCB group) and three locations that are the dominant distribution areas of P. chinensis s.s. (ZHB group). Their whole mitochondrial genomes were sequenced and analyzed. The differential analysis revealed that there were 339 fixed differential sites in the mitochondrial genome-coding region of P. chinensis s.s. and P. sichuanensis, among which the COI gene had the most differential sites (57), followed by ND5 (46), ND4 (38), and CYTB (37), while ATP8 had the least differential sites (4). The molecular genetic p-distance was calculated based on 13 protein-coding regions, and the genetic distance ranged from 0.001 to 0.018 in the ZHB group and from 0.001 to 0.006 in the SCB group, while the interspecies molecular genetic distance was 0.464–0.466 between the two groups. A phylogenetic maximum likelihood tree was constructed from 16 samples via tandem sequence of 13 protein-coding regions, and the topology showed that the ZHB and SCB groups formed separate clusters. A real-time PCR method was established based on the differences in the COI fragment, which can identify P. sichuanensis from P. chinensis s.s. effectively. This study presents objective evidence of the genetic differentiation between P. sichuanensis and P. chinensis s.s., and provides a method for identifying these two morphologically highly similar VL-transmitting sandflies. Full article

This research paper attempts to describe the transmission dynamic of zoonotic visceral leishmaniasis with the aid of a mathematical model by considering the asymptomatic stages in humans and animals. The disease is endemic in several countries. Data used in the research are obtained from the literature while some are assumed based on the disease dynamic. The consideration of both asymptomatic and the symptomatic infected individuals is incorporated in both humans and animals (reservoir), as well as lines of treatment for the human population. It is found that the model has two fixed points; the VL-free fixed point and the VL-endemic fixed point. Stability analysis of the fixed points shows that the VL-free fixed point is globally asymptotically stable whenever the basic reproduction number is less than one and the VL-endemic fixed point is globally asymptotically stable whenever the basic reproduction number is greater than one. Sensitivity analysis is conducted for the parameters in the basic reproduction number, and the profile of each state variable is also depicted using the data obtained from the literature and those assumed. The transmission probability from infected sandflies to animals, transmission probability from infected animals to sandflies, per capita biting rate of sandflies of animals, and rate of transfer from symptomatic infected animals to the recovered class are among the most sensitive parameters that have the greatest influence on the basic reproduction number. Moreover, the value of the basic reproduction number is obtained to be 0.98951, which may require further study, as the margin between potential disease control and outbreak is thin. Full article

The main priority in leishmaniasis-endemic countries is to find safer and more accessible treatments for this neglected disease. In this study, we focus on a drug repositioning strategy using molecular docking. New molecular entities (NMEs) approved by the FDA from 2019 to the present were analyzed. The therapeutic target was the sterol 14-alpha demethylase from Leishmania infantum. Of the 125 NMEs tested, 16 demonstrated greater affinity in virtual screening than the co-crystallized inhibitor (fluconazole). This approach offers a promising method for identifying new uses for existing drugs and provides a rapid way to discover safer treatments for leishmaniasis. Full article

The diagnosis of canine visceral leishmaniasis (CVL) presents a challenge due to a variety of non-specific clinical signs. The available tests have low sensitivity. This study aimed to standardize and evaluate the loop-mediated isothermal amplification technique with K26 target (K26-LAMP) for diagnosis of CVL in conjunctival swab (CS) DNA samples extracted through a silica column commercial kit (SW-kit) and boiling (SW-DB) and to compare sensitivity with conventional PCR (kDNA-cPCR) and quantitative real-time PCR (18S-qPCR). Clinical samples of CSs were collected from 54 dogs after reactive serology tests. Positive parasitological and/or histological tests were used as inclusion criteria for a sensitivity analysis. A total of 79.2% (43/54) of dogs without clinical signs or with mild, moderate, or severe clinical signs were included in the study. The sensitivity results of K26-LAMP, kDNA-cPCR, and 18S-qPCR were 72.1%, 81.4%, and 80.5% with the SW-kit and 97.2%, 95.2%, and 57.1% with SW-DB, respectively. In all techniques, the proportion of positives was higher in the group with severe clinical disease, with statistically significant differences in the K26-LAMP and 18S-qPCR techniques being seen with the SW-kit. The results obtained with LAMP for CS samples are promising and its performance is similar to other techniques. Full article

One of the main components of innate defense against invasive parasites is oxidative stress, which is brought on by reactive oxygen species (ROS). On the other hand, oxidative stressors serve two purposes: free radicals aid in the elimination of pathogens, but they can also set off inflammation, which leads to tissue damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that controls the expression of numerous genes involved in the body’s defense against oxidative stress brought on by aging, inflammation, tissue damage, and other pathological consequences. From cutaneous to visceral forms, Leishmania parasites invade macrophages and cause a wide range of human pathologies. Leishmania parasites have a wide range of adaptive mechanisms that disrupt several macrophage functions by altering host signaling pathways. An increasing amount of data are corroborating the idea that one of the primary antioxidant routes to counteract this oxidative burst against parasites is NRF2 signaling, which also interferes with immune responses. The nature and potency of the host immune response, as well as interactions between the invading Leishmania spp., will ascertain the course of infection and the parasites’ eventual survival or eradication. The molecular processes via which Nrf2 coordinates such intricate networks comprising various pathways remain to be completely understood. In light of NRF2’s significant contribution to oxidative stress, we examine the NRF2 antioxidant pathway’s activation mechanism in Leishmania infection in this review. Thus, this review will examine the relationship between Nrf2 signaling and leishmaniasis, as well as explore potential therapeutic strategies for modifying this system. Full article