Unraveling the role of natural killer cells in leishmaniasis.

NK cells are known as frontline responders that are efficient in combating several maladies as well as leishmaniasis caused by Leishmania spp. As such they are being investigated to be used for adoptive transfer therapy and vaccine. In spite of the lack of antigen-specific receptors at their surface, NK cells can selectively recognize pathogens, accomplished by the activation of the receptors on the NK cell surface and also as the result of their effector functions. Activation of NK cells can occur through interaction between TLR-2 expressed on NK cells and. LPG of Leishmania parasites. In addition, NK cell activation can occur by cytokines (e.g., IFN-γ and IL-12) that also lead to producing cytokines and chemokines and lysis of target cells. This review summarizes several evidences that support NK cells activation for controlling leishmaniasis and the potentially lucrative roles of NK cells during leishmaniasis. Furthermore, we discuss strategies of Leishmania parasites in inhibiting NK cell functions. Leishmania LPG can utilizes TLR2 to evade host-immune responses. Also, Leishmania GP63 can directly binds to NK cells and modulates NK cell phenotype. Finally, this review analyzes the potentialities to harness NK cells effectiveness in therapy regimens and vaccinations.

Treatment options for leishmaniasis.

Leishmaniasis is broadly classified into three types: cutaneous, mucocutaneous and visceral. The visceral form is most dangerous and can result in death. Although leishmaniasis is an ancient disease, its treatment is still challenging. Several drugs, differing in their cost, toxicity, treatment duration and emergence of drug resistance, are used for different types of leishmaniasis. To overcome these limitations, the search for newer drugs and other treatments continues. In this article, we discuss conventional drugs, other treatments, including newer options such as immunotherapy and immunochemotherapy, and future prospects for leishmaniasis treatment.

Larval excretion/secretion of dipters of Lucilia cuprina species induces death in promastigote and amastigote forms of Leishmania amazonensis.

Leishmaniasis is a neglected tropical disease that affects millions of people around the world. Larval excretion/secretion (ES) of the larvae of flies of the Calliphoridae family has microbicidal activity against Gram-positive and Gram-negative bacteria, in addition to some species of Leishmania. Our study aimed at assessing the in vitro efficacy of Lucilia cuprina larval ES against the promastigote and amastigote forms of Leishmania amazonensis, elucidating possible microbicidal mechanisms and routes of death involved. Larval ES was able to inhibit the viability of L. amazonensis at all concentrations, induce morphological and ultrastructural changes in the parasite, retraction of the cell body, roughness of the cytoplasmic membrane, leakage of intracellular content, ROS production increase, induction of membrane depolarization and mitochondrial swelling, the formation of cytoplasmic lipid droplets and phosphatidylserine exposure, thus indicating the possibility of apoptosis-like death. To verify the efficacy of larval ES on amastigote forms, we performed a phagocytic assay, measurement of total ROS and NO. Treatment using larval ES reduced the percentage of infection and the number of amastigotes per macrophage of lineage J774A.1 at all concentrations, increasing the production of ROS and TNF-α, thus indicating possible pro-inflammatory immunomodulation and oxidative damage. Therefore, treatment using larval ES is effective at inducing the death of promastigotes and amastigotes of L. amazonensis even at low concentrations.

Tropical Infections in the Context of Kidney Transplantation in Latin America.

Reports on tropical infections among kidney transplant (KT) recipients have increased in recent years, mainly because of the growing number of KT programs located in tropical and subtropical areas, and greater mobility or migration between different areas of the world. Endemic in emerging and developing regions, like most countries in Latin America, tropical infections are an important cause of morbidity and mortality in this population. Tropical infections in KT recipients may exhibit different pathways for acquisition compared with those in nonrecipients, such as transmission through a graft and reactivation of a latent infection triggered by immunosuppression. Clinical presentation may differ compared with that in immunocompetent patients, and there are also particularities in diagnostic aspects, treatment, and prognosis. KT patients must be screened for latent infections and immunized properly. Last, drug-drug interactions between immunosuppressive agents and drugs used to treat tropical infections are an additional challenge in KT patients. In this review, we summarize the management of tropical infections in KT patients.

Host immune response against leishmaniasis and parasite persistence strategies: A review and assessment of recent research.

Leishmaniasis, a neglected parasitic disease caused by a unicellular protozoan of the genus Leishmania, is transmitted through the bite of a female sandfly. The disease remains a major public health problem and is linked to tropical and subtropical regions, with an endemic picture in several regions, including East Africa, the Mediterranean basin and South America. The different causative species display a diversity of clinical presentations; therefore, the immunological data on leishmaniasis are both scarce and controversial for the different forms and infecting species of the parasite. The present review highlights the main immune parameters associated with leishmaniasis that might contribute to a better understanding of the pathogenicity of the parasite and the clinical outcomes of the disease. Our aim was to provide a concise overview of the immunobiology of the disease and the factors that influence it, as this knowledge may be helpful in developing novel chemotherapeutic and vaccine strategies.

Three decades of clinical trials on immunotherapy for human leishmaniases: a systematic review and meta-analysis.

Aim: Current treatments for leishmaniases are not satisfactory, thus alternatives are needed. We searched for clinical trials with immunotherapeutic approaches for patients with leishmaniasis. Materials & methods: Out of 205 articles, 24 clinical trials were selected, and eight submitted to meta-analysis. Results: A reduction in healing time was observed in patients with tegumentary leishmaniasis treated with pentavalent antimony plus granulocyte-macrophage colony-stimulating factor, and therapeutic vaccines. Overall meta-analysis indicated that immunotherapy associated with the standard chemotherapy generated a significantly reduced risk of treatment failure than the pentavalent antimony alone (p = 0.03). Conclusion: Our review confirmed the efficacy of immunotherapies for the treatment of cutaneous and visceral leishmaniasis and highlighted the importance of clinical trials using immunotherapies for leishmaniases.

Unraveling the Role of Immune Checkpoints in Leishmaniasis.

Leishmaniasis are Neglected Tropical Diseases affecting millions of people every year in at least 98 countries and is one of the major unsolved world health issues. Leishmania is a parasitic protozoa which are transmitted by infected sandflies and in the host they mainly infect macrophages. Immunity elicited against those parasites is complex and immune checkpoints play a key role regulating its function. T cell receptors and their respective ligands, such as PD-1, CTLA-4, CD200, CD40, OX40, HVEM, LIGHT, 2B4 and TIM-3 have been characterized for their role in regulating adaptive immunity against different pathogens. However, the exact role those receptors perform during Leishmania infections remains to be better determined. This article addresses the key role immune checkpoints play during Leishmania infections, the limiting factors and translational implications.

Immunotherapy in treatment of leishmaniasis.

Leishmaniasis caused by various species of protozoan transmitted by sand fly vectors occurs as a spectrum of clinical features including cutaneous, mucocutaneous and visceral forms. It is a geographically distributed parasitic disease and a major public health problem in the world. The clinical syndromes are highly variable depending on the parasite species, host genetics, vectors and environment. To date, there is no effective vaccine and traditional treatments are toxic, expensive with long administration duration and many adverse side effects and/or drug resistance. Instead of treatments based on chemotherapy, certain strategies aim to recover leishmaniasis and reduce the parasitic burden. Immunotherapy has focused on the induction of effective immune response to rapidly control the disease. Recent studies have indicated that a single dose of a suitable therapeutic vaccine induces a quick and lasting recovery in patients. Immunotherapy reduces the toxicity of drug and the emergence of resistance dramatically. It could be an effective addition to chemotherapy with a safe and potent drug compared with monotherapy, resulting in a prophylactic and therapeutic cure of leishmaniasis. This review has focused on treatment of leishmaniasis with particular emphasis on immunotherapy as an alternative to conventional drug treatment.

Potential therapeutic targets shared between leishmaniasis and cancer.

The association of leishmaniasis and malignancies in human and animal models has been highlighted in recent years. The misdiagnosis of coexistence of leishmaniasis and cancer and the use of common drugs in the treatment of such diseases prompt us to further survey the molecular biology of Leishmania parasites and cancer cells. The information regarding common expressed proteins, as possible therapeutic targets, in Leishmania parasites and cancer cells is scarce. Therefore, the current study reviews proteins, and investigates the regulation and functions of several key proteins in Leishmania parasites and cancer cells. The up- and down-regulations of such proteins were mostly related to survival, development, pathogenicity, metabolic pathways and vital signalling in Leishmania parasites and cancer cells. The presence of common expressed proteins in Leishmania parasites and cancer cells reveals valuable information regarding the possible shared mechanisms of pathogenicity and opportunities for therapeutic targeting in leishmaniasis and cancers in the future.

Immunotherapeutic Potential of Interleukin-32 and Trained Immunity for Leishmaniasis Treatment.

Neglected tropical diseases annually account for several million infections worldwide. Efficacious treatment for these poorly understood infectious diseases is often limited to ineffective, expensive, and toxic therapies such as the SbV used for leishmaniasis patients. Here, we review the latest discoveries and literature on the molecular pathways, cell types, and immune mediators involved in the immune response to infection with New World Leishmania spp. in humans and their interaction with the adaptive and innate immune system. Novel developments in the field of trained innate immunity and the recently described role of IL-32 are emphasized as potential immunotherapeutic treatments for the management of leishmaniasis.

Heat Shock Proteins as the Druggable Targets in Leishmaniasis: Promises and Perils.

Leishmania, the causative agent of leishmaniasis, is an intracellular pathogen that thrives in the insect gut and mammalian macrophages to complete its life cycle. Apart from temperature difference (26 to 37°C), it encounters several harsh conditions, including oxidative stress, inflammatory reactions, and low pH. Heat shock proteins (HSPs) play essential roles in cell survival by strategically reprogramming cellular processes and signaling pathways. HSPs assist cells in multiple functions, including differentiation, adaptation, virulence, and persistence in the host cell. Due to cyclical epidemiological patterns, limited chemotherapeutic options, drug resistance, and the absence of a vaccine, control of leishmaniasis remains a far-fetched dream. The essential roles of HSPs in parasitic differentiation and virulence and increased expression in drug-resistant strains highlight their importance in combating the disease. In this review, we highlighted the diverse physiological importance of HSPs present in Leishmania, emphasizing their significance in disease pathogenesis. Subsequently, we assessed the potential of HSPs as a chemotherapeutic target and underlined the challenges associated with it. Furthermore, we have summarized a few ongoing drug discovery initiatives that need to be explored further to develop clinically successful chemotherapeutic agents in the future.

Host Mast Cells in Leishmaniasis: Friend or Foe?

Mast cells (MCs) are skin-resident immune cells whose role in leishmaniasis has been recently explored. Researchers report varying inferences, that is, mast cells promote, eliminate, or have no role in leishmaniasis. This article discusses this heterogeneity in mast cell roles to facilitate potential therapeutic and vaccine interventions for these diseases.

Identification of Leishmania species in patients derived to the National Institute of Health, Peru. / Identificación de especies de Leishmania en pacientes derivados al Instituto Nacional de Salud del Perú.

In Peru, leishmaniasis is a metaxenic disease that represents a serious public health problem, due to its wide distribution and the number of people in danger of contracting the disease, being the vulnerable population mainly those with low economic resources. The study was conducted from patients who were derived to Peru's National Institute of Health between 2006 and 2011 so that the specialized diagnosis could be carried out. The identification of the species of infectious Leishmania was developed through the analysis of the High-Resolution Melting Analysis obtained from the genomic DNA of promastigotes and amastigotes, which allows to identify the species of Leishmania (Viannia) braziliensis, Leishmania (V.) guyanensis, Leishmania (V.) peruviana as more prevalent, in addition to Leishmania (V.) lainsoni and Leishmania (L.) amazonensis.

En el Perú, la leishmaniasis es una enfermedad metaxénica que representa un serio problema de salud pública, debido a su amplia distribución y al número de personas en riesgo de contraer la enfermedad, siendo la población vulnerable principalmente las personas de bajos recursos económicos. El estudio se realizó a partir de pacientes que fueron derivados al Instituto Nacional de Salud entre el 2006 y el 2011 para que se les realizara el diagnóstico especializado. La identificación de la especie de Leishmania infectante se desarrolló mediante el análisis de las curvas de disociación (HRMA) obtenidas a partir del ADN genómico de promastigotes y amastigotes, lo que permitió identificar las especies de Leishmania (Viannia) braziliensis, Leishmania (V.) guyanensis, Leishmania (V.) peruviana como las más prevalentes, además de Leishmania (V.) lainsoni y Leishmania (L.) amazonensis.

DNA flowerstructure co-localizes with human pathogens in infected macrophages.

Herein, we characterize the cellular uptake of a DNA structure generated by rolling circle DNA amplification. The structure, termed nanoflower, was fluorescently labeled by incorporation of ATTO488-dUTP allowing the intracellular localization to be followed. The nanoflower had a hydrodynamic diameter of approximately 300 nanometer and was non-toxic for all mammalian cell lines tested. It was internalized specifically by mammalian macrophages by phagocytosis within a few hours resulting in specific compartmentalization in phagolysosomes. Maximum uptake was observed after eight hours and the nanoflower remained stable in the phagolysosomes with a half-life of 12 h. Interestingly, the nanoflower co-localized with both Mycobacterium tuberculosis and Leishmania infantum within infected macrophages although these pathogens escape lysosomal degradation by affecting the phagocytotic pathway in very different manners. These results suggest an intriguing and overlooked potential application of DNA structures in targeted treatment of infectious diseases such as tuberculosis and leishmaniasis that are caused by pathogens that escape the human immune system by modifying macrophage biology.

Camel nanobodies: Promising molecular tools against leishmaniasis.

AIM: To characterize several anti-Leishmania tropica nanobodies and to investigate their effect on Leishmania infection. METHODS: Several immunological tests were implied to characterize five different (as confirmed by sequencing) anti-L tropica nanobodies (NbLt05, NbLt06, NbLt14, NbLt24 and NbLt36) against parasite lysates or intact cells from different stages, promastigotes and amastigotes. Direct inhibitory effect of these nanobodies on parasite infection cycle on macrophages was tested in cell culture. RESULTS: All the five nanobodies (with distinguished characteristics) were more specific to L tropica than to L major, but could equally recognize the lysate and the outer surface of the intact cells from the two main stages of the parasite. Nanobodies recognized several leishmania antigens (majorly between 75 and 63 kDa), and their proteinaceous nature was confirmed. Because of its role in leishmania life cycle, gp63 was considered a potential antigen candidate for nanobodies, and bioinformatics predicted such interaction. All nanobodies have a negative effect on the infectivity of L tropica, as they decreased the number of infected macrophages and the amastigotes inside those macrophages. CONCLUSION: Such anti-leishmania nanobodies, with outstanding characteristics and important target, can be of great use in the development of promising treatment strategies against leishmaniasis.

Identificación de especies de Leishmania en pacientes derivados al Instituto Nacional de Salud del Perú / Identification of Leishmania species in patients derived to the National Institute of Health, Peru

RESUMEN En el Perú, la leishmaniasis es una enfermedad metaxénica que representa un serio problema de salud pública, debido a su amplia distribución y al número de personas en riesgo de contraer la enfermedad, siendo la población vulnerable principalmente las personas de bajos recursos económicos. El estudio se realizó a partir de pacientes que fueron derivados al Instituto Nacional de Salud entre el 2006 y el 2011 para que se les realizara el diagnóstico especializado. La identificación de la especie de Leishmania infectante se desarrolló mediante el análisis de las curvas de disociación (HRMA) obtenidas a partir del ADN genómico de promastigotes y amastigotes, lo que permitió identificar las especies de Leishmania (Viannia) braziliensis, Leishmania (V.) guyanensis, Leishmania (V.) peruviana como las más prevalentes, además de Leishmania (V.) lainsoni y Leishmania (L.) amazonensis.

ABSTRACT In Peru, leishmaniasis is a metaxenic disease that represents a serious public health problem, due to its wide distribution and the number of people in danger of contracting the disease, being the vulnerable population mainly those with low economic resources. The study was conducted from patients who were derived to Peru's National Institute of Health between 2006 and 2011 so that the specialized diagnosis could be carried out. The identification of the species of infectious Leishmania was developed through the analysis of the High-Resolution Melting Analysis obtained from the genomic DNA of promastigotes and amastigotes, which allows to identify the species of Leishmania (Viannia) braziliensis, Leishmania (V.) guyanensis, Leishmania (V.) peruviana as more prevalent, in addition to Leishmania (V.) lainsoni and Leishmania (L.) amazonensis.

Immunotherapy in clinical canine leishmaniosis: a comparative update.

Leishmaniosis due to Leishmania infantum is a complex infection that can affect both humans and dogs, and present a wide range of clinical signs and clinicopathological abnormalities. The conventional treatment of this disease is challenging due to the fact that complete parasitological cure commonly does not occur. Furthermore, treatment of the disease with the conventionally used drugs has several shortcomings. These include the need for long-term treatment, side effects and the formation of drug resistance. Moreover, it is important to highlight that the host immune responses play a crucial role in the outcome of this infection. For this reason, the use of immunotherapy in clinical leishmaniosis to improve the result of treatment with the conventional anti-leishmanial drugs by enhancing the immune response is imperative. The aim of this review is to provide a comparative overview of the wide range of immunotherapeutical approaches and strategies for the treatment of L. infantum infection in animals focusing on dogs.

Antimicrobial Peptides-based Nanostructured Delivery Systems: An Approach for Leishmaniasis Treatment.

BACKGROUND: Leishmaniasis is a major health problem mainly in tropical and subtropical areas worldwide, although in the last decades it has been treated with the use of conventional drugs such as amphotericin, the emergence of multidrug-resistant strains has raised a warning signal to the public health systems thus a new call for the creation of new leishmanicidal drugs is needed. METHODS: The goal of this review was to explore the potential use of antimicrobial peptides-based nanostructured delivery systems as an approach for leishmaniasis treatment. RESULTS: Within these new potential drugs, human host defense peptides (HDP) can be included given their remarkable antimicrobial activity and their outstanding immunomodulatory functions for the therapy of leishmaniasis. CONCLUSION: Though several approaches have been done using these peptides, new ways for delivering HDPs need to be analyzed, such is the case for nanotechnology.