Recent advances and new strategies on leishmaniasis treatment Roatt, Bruno Mendes; de Oliveira Cardoso, Jamille Mirelle; De Brito, Rory Cristiane Fortes ...
Applied microbiology and biotechnology,
11/2020, Letnik:
104, Številka:
21
Journal Article
Recenzirano
Leishmaniasis is one of the most important tropical neglected diseases according to the World Health Organization. Even after more than a century, we still have few drugs for the disease therapy and ...their great toxicity and side effects put in check the treatment control program around the world. Moreover, the emergence of strains resistant to conventional drugs, co-infections such as HIV/
Leishmania
spp., the small therapeutic arsenal (pentavalent antimonials, amphotericin B and formulations, and miltefosine), and the low investment for the discovery/development of new drugs force researchers and world health agencies to seek new strategies to combat and control this important neglected disease. In this context, the aim of this review is to summarize new advances and new strategies used on leishmaniasis therapy addressing alternative and innovative treatment paths such as physical and local/topical therapies, combination or multi-drug uses, immunomodulation, drug repurposing, and the nanotechnology-based drug delivery systems.
Key points
•
The treatment of leishmaniasis is a challenge for global health agencies.
•
Toxicity, side effects, reduced therapeutic arsenal, and drug resistance are the main problems.
•
New strategies and recent advances on leishmaniasis treatment are urgent.
•
Immunomodulators, nanotechnology, and drug repurposing are the future of leishmaniasis treatment.
Various factors contribute to the urbanization of the visceral leishmaniasis (VL), including the difficulties of implementing control measures relating to the domestic reservoir. The aim of this ...study was to determine the prevalence of canine visceral leishmaniasis in an urban endemic area in Brazil and the factors associated with Leishmania infantum infection among seronegative and PCR-positive dogs.
A cross-sectional study was conducted in Belo Horizonte, Minas Gerais, Brazil. Blood samples were collected from 1,443 dogs. Serology was carried out by using two enzyme-linked immunosorbent assays (Biomanguinhos/FIOCRUZ/RJ and "in house"), and molecular methods were developed, including PCR-RFLP. To identify the factors associated with early stages of infection, only seronegative (n = 1,213) animals were evaluated. These animals were divided into two groups: PCR-positive (n = 296) and PCR-negative (n = 917) for L. infantum DNA. A comparison of these two groups of dogs taking into consideration the characteristics of the animals and their owners was performed. A mixed logistic regression model was used to identify factors associated with L. infantum infection.
Of the 1,443 dogs examined, 230 (15.9%) were seropositive in at least one ELISA, whereas PCR-RFLP revealed that 356 animals (24.7%) were positive for L. infantum DNA. Results indicated that the associated factors with infection were family income<twice the Brazilian minimum salary (OR 2.3; 95%CI 1.4-3.8), knowledge of the owner regarding the vector (OR 1.9; 95%CI 1.1-3.4), the dog staying predominantly in the backyard (OR 2.2; 95%CI 1.1-4.1), and a lack of previous serological examination for VL (OR 1.5; 95%CI 1.1-2.3).
PCR detected a high prevalence of L. infantum infection in dogs in an area under the Control Program of VL intervention. Socioeconomic variables, dog behavior and the knowledge of the owner regarding the vector were factors associated with canine visceral leishmaniasis (CVL). The absence of previous serological examination conducted by the control program was also associated with L. infantum infection. It is necessary to identify the risk factors associated with CVL to understand the expansion and urbanization of VL.
Recent advances and new strategies in Leishmaniasis diagnosis De Brito, Rory Cristiane Fortes; Aguiar-Soares, Rodrigo Dian de Oliveira; Cardoso, Jamille Mirelle de Oliveira ...
Applied microbiology and biotechnology,
10/2020, Letnik:
104, Številka:
19
Journal Article
Recenzirano
Leishmaniasis is a set of complex and multifaceted syndromes, with different clinical manifestations, caused by different species of the genus
Leishmania
spp. that can be characterized by at least ...four syndromes: visceral leishmaniasis (VL, also known as kala-azar), post-kala-azar dermal leishmaniasis (PKDL), cutaneous leishmaniasis (CL), and mucocutaneous leishmaniasis (MCL). Among the most serious clinical forms, VL stands out, which causes the death of around 59,000 people annually. Fast and accurate diagnosis in VL is essential to reduce the disease’s morbidity and mortality. There are a large number of diagnostic tests for leishmaniasis, however they do cross-react with other protozoa and their sensitivity changes according to the clinical form of the disease. Thus, it is essential and necessary to provide a diagnosis that is sufficiently sensitive to detect asymptomatic infected individuals and specific to discriminate individuals with other infectious and parasitic diseases, thus enabling more accurate diagnostic tools than those currently used. In this context, the aim of this review is to summarize the conventional diagnostic tools and point out the new advances and strategies on visceral and cutaneous leishmaniasis diagnosis.
In Brazil, case-fatality rates attributable to visceral leishmaniasis (VL) are high and knowledge of the risk factors associated with death may help reduce mortality. The aim of this study was to ...construct and validate a scoring system for prognosis of death from VL by using all cases reported in Brazil from 2007 to 2011.
In this historical cohort study, 18,501 VL cases were analyzed; of these, 17,345 cases were cured and 1,156 cases caused death. The database was divided into two series: primary (two-thirds of cases), to develop the model score, and secondary (one-third of cases), to validate the scoring system. Multivariate logistic regression models were performed to identify factors associated with death from VL, and these were included in the scoring system.
The factors associated with death from VL were: bleeding (score 3); splenomegaly (score 1); edema (score 1); weakness (score 1); jaundice (score 1); Leishmania-HIV co-infection (score 1); bacterial infection (score 1); and age (≤0.5 years score 5; >0.5 and ≤1 score 2; >19 and ≤50 score 2; >50 and <65 score 3; ≥65 score 5). It was observed that patients with a score of 4 had a probability of death of approximately 4.5% and had a worse prognosis. The sensitivity, specificity, and accuracy of this score were 89.4, 51.2, and 53.5, respectively.
The scoring system based on risk factors for death showed good performance in identifying patients with signs of severity at the time of clinical suspicion of VL and can contribute to improving the surveillance system for reducing case fatalities. The classification of patients according to their prognosis for death may assist decision-making regarding the transfer of the patients to hospitals more capable of handling their condition, admission to the intensive care unit, and adequate support and specific treatment.
Infection caused by Mayaro virus (MAYV) is responsible for causing acute nonspecific fever, in which the majority of patients develop incapacitating and persistent arthritis/arthralgia. Mayaro fever ...is a neglected and underreported disease without treatment or vaccine, which has gained attention in recent years after the competence of Aedes aegypti to transmit MAYV was observed in the laboratory, coupled with the fact that cases are being increasingly reported outside of endemic forest areas, calling attention to the potential of an urban cycle arising in the near future. Thus, to mitigate the lack of information about the pathological aspects of MAYV, we previously described the involvement of oxidative stress in MAYV infection in cultured cells and in a non-lethal mouse model. Additionally, we showed that silymarin, a natural compound, attenuated MAYV-induced oxidative stress and inhibited MAYV replication in cells. The antioxidant and anti-MAYV effects prompted us to determine whether silymarin could also reduce oxidative stress and MAYV replication after infection in an immunocompetent animal model. We show that infected mice exhibited reduced weight gain, hepatomegaly, splenomegaly, anaemia, thrombocytopenia, leukopenia, increased liver transaminases, increased pro-inflammatory cytokines and liver inflammation, increased oxidative damage biomarkers, and reduced antioxidant enzyme activity. However, in animals infected and treated with silymarin, all these parameters were reversed or significantly improved, and the detection of viral load in the liver, spleen, brain, thigh muscle, and footpad was significantly reduced. This work reinforces the potent hepatoprotective, antioxidant, anti-inflammatory, and antiviral effects of silymarin against MAYV infection, demonstrating its potential against Mayaro fever disease.
•Silymarin improves MAYV infection in BALB/c mice.•Silymarin protects mice from liver damage, oxidative stress, inflammation, and virus replication after MAYV infection.•Promising potential of silymarin in the therapeutic treatment of Mayaro fever.
Hematological analysis has limited applications for disease diagnosis in Leishmania infantum-infected dogs, but it can be very important in evaluating the clinical forms of the disease and in ...understanding the evolution of canine visceral leishmaniasis (CVL) pathogenesis. Recently, we demonstrated that alterations in leucopoiesis and erythropoiesis are related to clinical status and bone marrow parasite density in dogs naturally infected by L. infantum. To further characterize these alterations, we evaluated the association between the hematological parameters in bone marrow and peripheral blood alterations in groups of L. infantum-infected dogs: asymptomatic I (AD-I: serum negative/PCR+), asymptomatic II (AD-II: serum positive), oligosymptomatic (OD), and symptomatic (SD). Results were compared with those from noninfected dogs (NID). The SD group was found to present a decrease in erythropoietic lineage with concomitant reductions in erythrocytes, hemoglobin, and hematocrit parameters, resulting in anemia. The SD group also had increased neutrophils and precursors and decreased band eosinophils and eosinophils, leading to peripheral blood leucopenia. In the AD-II group, lymphocytosis occurred in both the peripheral blood and the bone marrow compartments. The SD group exhibited lymphocytosis in the bone marrow, with lymphopenia in the peripheral blood. In contrast, the AD-I group, showed no significant changes suggestive of CVL, presenting normal counts in bone marrow and peripheral blood. Our results showed for the first time that important changes in hematopoiesis and hematological parameters occur during ongoing CVL in naturally infected dogs, mainly in symptomatic disease. Taken together, our results based on myelogram and hemogram parameters enable better understanding of the pathogenesis of the anemia, lymphocytosis, and lymphopenia, as well as the leucopenia (eosinopenia and monocytopenia), that contribute to CVL prognosis.
An accurate diagnosis of visceral leishmaniasis is an essential tool for control of the disease. While serologic methods are very useful, these conventional methodologies still present limitations in ...terms of sensitivity and specificity. The use of flow cytometry is a worldwide trend in the development of high-performance diagnostic methods. Herein, we describe a new flow cytometry serology test, characterized by the employment of the Cytometric Bead Array microspheres
A4
and
E4
coated with the recombinant antigens rLci1A and rLci2B respectively, to improve the serodiagnosis of canine visceral leishmaniasis. The tests were conducted in a wide variety of sera groups (
n
= 140), where the diagnostics development would be optimized accounting not just the ability to identify infected dogs with different clinical status, but also to exclude cross-reaction and differentiate vaccinated dogs from dogs infected. Serological testing of the antigenic system
A4
–rLci1A showed a sensitivity of 90.0% and specificity of 75%, while the
E4
–rLci2B testing demonstrated a sensitivity of 95.0% and specificity of 82.5%. The use of a multiplex assay of
A4
–rLci1A and
E4
–rLci2B, resulted in a diagnostic improvement, with a sensitivity of 95.0% and specificity of 91.2%. Our results show that this novel flow cytometry serology test is a viable tool for sensitive and specific serodiagnosis. Notably, the combination of distinct antigenic systems allows us to test for antibodies to multiple recombinant antigens from a single serum sample. This benefit emphasizes the importance of this methodology as an alternative in the serological diagnosis.
Visceral leishmaniasis is the most severe form of leishmaniasis. Worldwide, approximately 20% of zoonotic human visceral leishmaniasis is caused by Leishmania infantum, also known as Leishmania ...chagasi in Latin America. Current diagnostic methods are not accurate enough to identify Leishmania-infected animals and may compromise the effectiveness of disease control. Therefore, we aimed to produce and test two recombinant multiepitope proteins as a means to improve and increase accuracy in the diagnosis of canine visceral leishmaniasis (CVL).
Ten antigenic peptides were identified by CVL ELISA in previous work. In the current proposal, the coding sequences of these ten peptides were assembled into a synthetic gene. Furthermore, other twenty peptides were selected from work by our group where good B and T cell epitopes were mapped. The coding sequences of these peptides were also assembled into a synthetic gene. Both genes have been cloned and expressed in Escherichia coli, producing two multiepitope recombinant proteins, PQ10 and PQ20. These antigens have been used in CVL ELISA and were able to identify asymptomatic dogs (80%) more effectively than EIE-LVC kit, produced by Bio-Manguinhos (0%) and DPP kit (10%). Moreover, our recombinant proteins presented an early detection (before PCR) of infected dogs, with positivities ranging from 23% to 65%, depending on the phase of infection in which sera were acquired.
Our study shows that ELISA using the multiepitope proteins PQ10 and PQ20 has great potential in early CVL diagnosis. The use of these proteins in other methodologies, such as immunochromatographic tests, could be beneficial mainly for the detection of asymptomatic dogs.
This case report presents an 82-year-old woman with decreased visual acuity. Clinical and multimodal evaluation revealed an elevated macular lesion with choroidal thickening. Fluorescein angiography ...and optical coherence tomography (OCT) showed characteristic patterns of choroidal metastasis. Thoracic CT scan confirmed a nodular mass in the right hilus, suggesting bronchogenic neoplastic process. A pleural biopsy demonstrated malignant neoplasia with characteristics of adenocarcinoma, and immunohistochemistry was positive for thyroid transcription factor 1 (TTF-1). These findings emphasize the critical role of ophthalmological examinations in early detection and intervention, as choroidal tissue is highly susceptible to metastasis, particularly from breast and lung cancers. Additionally, the poor prognosis associated with metastatic lung cancer underscores the urgency for prompt action.
Phthiriasis palpebrarum is a rare parasitosis of the eyelashes caused by Phthirus pubis. This report describes an atypical case of this disease.A 72-year-old female patient suffered prolonged ...symptoms of severe left eye pruritus for 18 months, refractory to conventional eyelid hygienic measures, and anti-histaminic and corticosteroid medications. Slit-lamp examination showed multiple translucent oval structures adherent to the upper eyelashes, and 18 crab-like lice, which were mechanically removed and characterized as Phthirus pubis. Treatment was started with corticosteroid and antibiotic ointment, vaseline, and Blephademodex® wipes (Laboratoires Théa, Auvergne-Rhone-Alpes, France). After 2 weeks, all symptoms had subsided completely.Although rare, phthiriasis palpebrarum may be easily confused with frequent palpebral pathologies like blepharitis. A careful slit-lamp examination is central for proper evaluation and diagnosis. Mechanical removal of the lice is the most effective treatment but should be complemented by topical and/or systemic treatment. This report presented an atypical case of this disease.
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