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Reevaluation of treatment guidelines for Old and New World leishmaniasis is urgently needed on a global basis because treatment failure is an increasing problem. Drug resistance is a fundamental determinant of treatment failure, although other factors also contribute to this phenomenon, including the global HIV/AIDS epidemic with its accompanying impact on the immune system. Pentavalent antimonials have been used successfully worldwide for the treatment of leishmaniasis since the first half of the 20th century, but the last 10 to 20 years have witnessed an increase in clinical resistance, e.g., in North Bihar in India. In this review, we discuss the meaning of \"resistance\" related to leishmaniasis and discuss its molecular epidemiology, particularly for Leishmania donovani that causes visceral leishmaniasis. We also discuss how resistance can affect drug combination therapies. Molecular mechanisms known to contribute to resistance to antimonials, amphotericin B, and miltefosine are also outlined.

Background Cutaneous leishmaniasis (CL) is an endemic disease in Brazil that is highly prevalent in the northern region of the country. Although there is a continuous and growing number of cases registered in the state of Roraima, there is limited information regarding the species of Leishmania that affect the human population. In this study, we aimed to characterize which Leishmania species cause human disease in those presenting with cutaneous leishmaniasis in endemic areas of the State of Roraima. Methods We conducted a prospective surveillance study between 2016 to 2018 in health centers located in the State of Roraima, Brazil. Participants with clinical suspicion of CL were enrolled and provided lesion samples for parasitological detection by microscopy. A subset of the samples was tested by polymerase chain reaction and sequencing of the internal transcribed spacer 1 (ITS-1 PCR) for molecular species identification. Results A total of 262 participants were enrolled in this study. Of those, 129 (49.27%) were positive by parasitological examination. Most positive subjects (81.58%) were male, and most cases presented a single lesion (80.26%). ITS-1 PCR and sequencing on a subset of 76 samples allowed us to detect nine different species of Leishmania : L. (V.) braziliensis , L (V.) panamensis , L. (V.) guyanensis , L. (V.) naiffi , L. (V.) shawi , L.(V.) utingensis , L. (V.) lindenbergi, L. (L.) amazonensis and L. (L.) mexicana . Conclusions Our study provides the first assessment of circulating species of Leishmania in the State of Roraima, Brazil, and shows the high diversity in this region. This study opens the path for further research on the transmission of leishmaniasis in the northernmost Brazilian State including vector and reservoir surveillance as well as for intensification of investigation and control activities against CL in the region. Graphical Abstract

Leishmaniasis has been considered as emerging and re-emerging disease, and its increasing global incidence has raised concerns. The great clinical diversity of the disease is mainly determined by the species. In several American countries, tegumentary leishmaniasis (TL) is associated with both Leishmania amazonensis and L. braziliensis, while visceral leishmaniasis (VL) is associated with L. (L.) infantum. The major molecules that determine the most diverse biological variations are proteins. In the present study, through a DIGE approach, we identified differentially abundant proteins among the species mentioned above. We observed a variety of proteins with differential abundance among the studied species; and the biological networks predicted for each species showed that many of these proteins interacted with each other. The prominent proteins included the heat shock proteins (HSPs) and the protein network involved in oxide reduction process in L. amazonensis, the protein network of ribosomes in L. braziliensis, and the proteins involved in energy metabolism in L. infantum. The important proteins, as revealed by the PPI network results, enrichment categories, and exclusive proteins analysis, were arginase, HSPs, and trypanothione reductase in L. amazonensis; enolase, peroxidoxin, and tryparedoxin1 in L. braziliensis; and succinyl-CoA ligase [GDP -forming] beta-chain and transaldolase in L. infantum.

New biomarkers are needed for monitoring the effectiveness of treatment for visceral leishmaniasis (VL). They might also improve the detection of the asymptomatic population in endemic areas. This paper examines the IL-2, IFN-γ, IFN-γ-induced protein 10 (IP-10), and monokine-induced-by-IFN-γ (MIG) levels in whole blood-stimulated with soluble antigen (SLA)-taken from asymptomatic individuals and patients treated for VL living in a post-outbreak ( ) area in Spain, and in an endemic ( ) area of Bangladesh. IP-10 was found to be an accurate global marker of asymptomatic subjects with positive cellular/humoral tests, while MIG was found to be a better marker of contact with than IL-2 but no for those with . Determining IP-10, MIG, and IFN-γ levels proved useful in monitoring the cellular immune response following treatment for active disease caused by .

In North African countries, cutaneous leishmaniasis transmission has been increasing since the 1980s, with a significant increase in the incidence of cases and a spread of the geographical distribution. The disease currently represents a major public health problem with a productivity gap and an impediment for development, which results in dramatic socioeconomic and psycho-sanitary impacts. The incidence is more than thousands of cases every year in Algeria, Libya, Morocco, and Tunisia. In Egypt, only a few dozen cases per year are reported, mainly in the Sinai Peninsula. Three Leishmania species, associated with distinct eco-epidemiological and clinical patterns, are involved, namely Leishmania infantum, L. major, and L. tropica. However, L. major is by far the most frequent in Algeria, Libya, and Tunisia, with more than 90% of the registered cases. It is mainly encountered in rural areas under semi-arid, arid and Saharan climates. Leishmania tropica is more prevalent in Morocco, reaching 30–40% of isolates in some districts. Much data is still missing concerning the risk factors of the infection and the lesion development, as well as vector and reservoir ecology and behavior. The knowledge of such parameters, following multidisciplinary and integrated approaches, is crucial for better management and control of the disease, that also faces a lack of resources and efficient control measures. La leishmaniose cutanée est émergente en Afrique du Nord depuis le début des années 80 avec une augmentation importante de l’incidence des cas et une extension de la répartition géographique. La maladie constitue un problème majeur de santé publique, avec un impact négatif sur la productivité et un handicap pour le développement, qui altère les conditions socio-économiques et psycho-sanitaires. L’incidence dépasse les milliers de cas chaque année en Algérie, Libye, Maroc et Tunisie. Elle est plus faible en Égypte, limitée à quelques dizaines de cas principalement dans le Sinaï. Trois espèces de Leishmania, associées à des caractéristiques environnementales, épidémiologiques et cliniques distinctes, sont responsables de la maladie, à savoir Leishmania infantum, L. major et L. tropica. Leishmania major est de loin la plus fréquente en Algérie, Libye et Tunisie avec plus de 90 % des cas enregistrés. Elle sévit principalement dans les zones rurales des étages bioclimatiques semi-arides, arides et sahariens. Leishmania tropica est plus répandue au Maroc où elle est responsable de 30 à 40 % des cas dans certaines régions. De nombreuses données manquent encore concernant les facteurs de risque de l’infection, la pathogénie des espèces en cause, et l’écologie et le comportement des vecteurs et réservoirs. La connaissance de ces paramètres, grâce à une approche multidisciplinaire et intégrée, est fondamentale pour un contrôle de la maladie, qui reste par ailleurs également confronté aux insuffisances des ressources et des mesures efficaces de lutte. داء اللايشمانيا الجلدي من الأمراض الناشئة في بلدان شمال إفريقيا والعدد الإجمالي للحالات في ارتفاع متواصل مع انتشار جغرافي للوباء منذ بداية الثمانيات. يعد هذا الداء من المشاكل الصحية ذات الأولوية في المغرب العربي ولو انه اقل حدة في القطر المصري ولهذا الداء تأثيرات مباشرة صحية واجتماعية واقتصادية، كما له انعكاسات سلبية على النمو والتطور في البلدان المتضررة. هناك ثلاثة أنواع من طفيلي اللايشمانيا تتسبب في المرض في شمال إفريقيا و ترتبط كل منها بخاصيات بيئية و وبائية و سريرية، وهي اللايشمانيا الطفيلية (L. infantum) و اللايشمانيا الرائدة (L. major) و اللايشمانيا المدارية.(L. tropica) اللايشمانيا الرائدة هي الأكثر انتشارا بتونس والجزائر وليبيا حيث تتسبب في أكثر من %90 من الحالات المرضية و تتوزع هده الحالات بالأخص في المناطق الريفية و القاحلة والصحراوية. و تختص الوضعية الوبائية في المغرب بارتفاع نسبي لعدد الحالات المنسوبة لللايشمانيا المدارية (30 إلى %40) في حين تبقى اللايشمانيا الرائدة أكثر تفشيا. البحوث العلمية والحملات الميدانية يجب أن تكثف لتحسين وإتمام المعلومات خاصة تلك المتصلة بالخازن و الفواصد الناقلة وخصوصياتها البيئية. لهذه المعلومات أهمية قصوى في مجابهة هذا المرض الذي يبقى التغلب عليه رهن توفير الإمكانيات المادية واللوجستية من ناحية والحلول الفعالة من ناحية أخرى.

Skin ulcers are most commonly due to circulatory or metabolic disorders and are a major public health concern. In developed countries, chronic wounds affect more than 1 % of the population and their incidence is expected to follow those observed for diabetes and obesity. In tropical and subtropical countries, an additional issue is the occurrence of ulcers of infectious origins with diverse etiologies. While the severity of cutaneous Leishmaniasis correlates with protective immune responses, Buruli ulcers caused by Mycobacterium ulcerans develop in the absence of major inflammation. Based on these two examples, this review aims to demonstrate how studies on microorganism-provoked wounds can provide insight into the molecular mechanisms controlling skin integrity. We highlight the potential interest of a mouse model of non-inflammatory skin ulceration caused by intradermal injection of mycolactone, an original lipid toxin with ulcerative and immunosuppressive properties produced by M. ulcerans.

Hybridization events within the genus have been documented; however, their impact on the infection dynamics of hybrids remains poorly understood. In this study, we compared the infection dynamics caused by a hybrid parasite, ( ) / ( ) , with those caused by its parental species, ( ) and ( ) , in BALB/c mice. Balb/c mice were inoculated with stationary-phase promastigote forms of each parasite. Lesion development and parasite load were monitored longitudinally, and cytokine production was assessed at 35 days post-infection (PI). The infection with the hybrid parasite induced a more rapid and evident progression, attaining its largest dimension between days 14 and 28 days PI, followed by regression. In contrast, infection with . ( .) resulted in a continuous increase in swelling, whereas . ( .) caused only mild swelling. Parasite loads in skin and lymph nodes were comparable across groups, though the hybrid parasite exhibited a significant increase in parasite burden from day 35 PI onwards. The immunologic response of hybrid parasite infection was associated with reduced gamma interferon (IFN-γ) and elevated interleukin 4 (IL-4) production compared to parental species and controls (P < 0.05), with no significant differences observed in interleukin 12 (IL-12p40) or interleukin 10 (IL-10). Infection with . ( .) led to decreased IFN-γ in lymph nodes and increased IL-4 production in both skin and lymph nodes, whereas . ( .) infection did not significantly alter cytokine profiles. Together, these findings provide important insights into the distinct biological behavior of the hybrid parasite and its parental species, underscoring the relevance of hybridization in shaping host-parasite interactions and advancing our understanding of leishmaniasis within complex eco-epidemiological settings.

Significance Peroxiredoxins (Prxs) are highly abundant proteins, which serve two seemingly mutually exclusive roles as peroxidases and molecular chaperones. Little is known about the precise mechanism of Prxs’ activation as chaperone and the physiological significance of this second function. Here we demonstrate that in Leishmania infantum , reduced Prx provides a crucial, stress-specific chaperone reservoir, which is activated rapidly upon exposure to unfolding stress conditions. Once activated, Prx protects a wide range of different clients against protein unfolding. Clients are bound in the center of the decameric ring, providing experimental evidence for previous claims that Prxs serve as likely ancestors of chaperonins. Interference with client binding impairs Leishmania infectivity, providing compelling evidence for the in vivo importance of Prx’s chaperone function. Cytosolic eukaryotic 2-Cys-peroxiredoxins have been widely reported to act as dual-function proteins, either detoxifying reactive oxygen species or acting as chaperones to prevent protein aggregation. Several stimuli, including peroxide-mediated sulfinic acid formation at the active site cysteine, have been proposed to trigger the chaperone activity. However, the mechanism underlying this activation and the extent to which the chaperone function is crucial under physiological conditions in vivo remained unknown. Here we demonstrate that in the vector-borne protozoan parasite Leishmania infantum , mitochondrial peroxiredoxin (Prx) exerts intrinsic ATP-independent chaperone activity, protecting a wide variety of different proteins against heat stress-mediated unfolding in vitro and in vivo. Activation of the chaperone function appears to be induced by temperature-mediated restructuring of the reduced decamers, promoting binding of unfolding client proteins in the center of Prx’s ringlike structure. Client proteins are maintained in a folding-competent conformation until restoration of nonstress conditions, upon which they are released and transferred to ATP-dependent chaperones for refolding. Interference with client binding impairs parasite infectivity, providing compelling evidence for the in vivo importance of Prx’s chaperone function. Our results suggest that reduced Prx provides a mitochondrial chaperone reservoir, which allows L. infantum to deal successfully with protein unfolding conditions during the transition from insect to the mammalian hosts and to generate viable parasites capable of perpetuating infection.

Background Leishmania use exosomes to communicate with their mammalian hosts and these secreted vesicles appear to contribute to pathogenesis by delivering protein virulence factors to macrophages. In other eukaryotes, exosomes were found to carry RNA cargo, such as mRNAs and small non-coding RNAs, capable of altering recipient cell phenotype. Whether leishmania exosomes also contain RNAs which they are able to deliver to bystander cells is not known. Here, we show that leishmania exosomes indeed contain RNAs and compare and contrast the RNA content of exosomes released by Leishmania donovani and Leishmania braziliensis . Results We purified RNA from exosomes collected from axenic amastigote culture supernatant and found that when compared with total leishmania RNA, exosomes mainly contained short RNA sequences. Exosomes with intact membranes were capable of protecting their RNA cargo from degradation by RNase. Moreover, exosome RNA cargo was delivered to host cell cytoplasm in vitro . Sequencing of exosomal RNA indicated that the majority of cargo sequences were derived from non-coding RNA species such as rRNA and tRNA. In depth analysis revealed the presence of tRNA-derived small RNAs, a novel RNA type with suspected regulatory functions. Northern blotting confirmed the specific and selective enrichment of tRNA-derived small RNAs in exosomes. We also identified a number of novel transcripts, which appeared to be specifically enriched in exosomes compared to total cell RNA. In addition, we observed the presence of sequences mapping to siRNA-coding regions in L. braziliensis , but not in L. donovani exosomes. Conclusions These results show that leishmania exosomes are selectively and specifically enriched in small RNAs derived almost exclusively from non-coding RNAs. These exosomes are competent to deliver their cargo of novel, potential small regulatory RNAs to macrophages where they may influence parasite-host cell interactions. The remarkably high degree of congruence in exosomal RNA content between L. donovani and L. braziliensis , argues for the presence of a conserved mechanism for exosomal RNA packaging in leishmania. These findings open up a new avenue of research on non-canonical, small RNA pathways in this trypanosomatid, which may elucidate pathogenesis and identify novel therapeutic approaches.

Background Leishmaniasis is a serious health problem in some parts of the world. In spite of the many known leishmaniasis control measures, the disease has continued to increase in endemic areas, and no effective vaccine has been discovered. Methods In this study, Leishmania tarentulae was used as a living factory for the production of two LACK and KMP11 immunogenic antigens in the mice body, and safety profiles were investigated. The sequences of the KMP11 and LACK L. major antigens were synthesized in the pLEXSY-neo 2.1 plasmid and cloned into E. coli strain Top10, and after being linearized with the SwaI enzyme, they were transfected into the genome of L. tarentolae . The L. tarentolae-LACK/KMP11/EGFP in the stationary phase with CpG ODN as an adjuvant was used for vaccination in BALB/c mice. Vaccination was performed into the left footpad. Three weeks later, the booster was injected in the same manner. To examine the effectiveness of the injected vaccine, pathogenic L. major (MRHO/IR/75/ER) was injected into the right footpad of all mice three weeks following the booster vaccination. In order to assess humoral immunity, the levels of IgG1, and IgG2a antibodies before and 6 weeks after the challenge were studied in the groups. In addition, in order to investigate cellular immunity in the groups, the study measured IFN-γ, IL-5, TNF-α, IL-6 and IL-17 cytokines before, 3 weeks and 8 weeks after the challenge, and also the parasite load in the lymph node with real-time PCR. Results The lowest level of the parasitic load was observed in the G1 group (mice vaccinated with L. tarentolae-LACK/KMP11/EGFP with CpG) in comparison with other groups ( L. tarentolae -LACK/KMP11/EGFP +non-CpG (G2); L. tarentolae -EGFP + CpG (G3, control); L. tarentolae -EGFP + non-CpG (G4, control); and mice injected with PBS (G5, control). Moreover, the evaluation of immune response showed a delayed-type hypersensitivity towards Th1. Conclusions According to the results of this study, the live recombinant vaccine of L. tarentolae-LACK/KMP11/EGFP with the CpG adjuvant reduced the parasitic load and footpad induration in infected mice. The long-term effects of this vaccine can be evaluated in volunteers as a clinical trial in future planning.