ARTICLE | doi:10.20944/preprints202212.0223.v1
Subject: Life Sciences, Biotechnology Keywords: Leishmaniasis; recombinant chimeric protein; serodiagnosis; visceral leishmaniasis; humans; dogs
Online: 13 December 2022 (02:38:38 CET)
Background: Visceral leishmaniasis (VL) is s critical public health problem in over ninety countries. The control measures adopted in Brazil have been insufficient when it comes to preventing the spread of this neglected disease. In this context, a precise diagnosis of VL in dogs and humans could help to reduce the number of cases of this disease. Distinct studies for the diagnosis of VL have used single recombinant proteins in serological assays; however, results have been variable, mainly in the sensitivity of the antigens. The development of multiepitope-based proteins could be relevant in solving such a problem. Methods: A chimeric protein (rMELEISH) was constructed based on amino acid sequences from kinesin 39 (k39), alpha-tubulin, and heat shock proteins HSP70 and HSP 83.1, and tested in ELISA for the detection of L. infantum infection in humans and dogs. Results: rMELEISH was able to discriminate between VL cases and cross-reactive diseases and healthy samples, with sensitivity and specificity values of 100% as compared to the use of a soluble Leishmania antigenic extract (SLA). Conclusions: Preliminary data suggest that the rMELEISH protein presents a potential to be tested in future studies against a larger serological panel for the diagnosis of canine and human VL.
ARTICLE | doi:10.20944/preprints202211.0275.v1
Subject: Biology, Animal Sciences & Zoology Keywords: visceral leishmaniasis; nanotechnology; vaccine
Online: 15 November 2022 (06:15:45 CET)
Visceral leishmaniasis (VL)is a fatal disease caused by the protozoa Leishmania infantum for which dogs are the main reservoirs. A vaccine against canine visceral leishmaniasis (CVL) could be an important tool in the control of human and CVL by reducing the infection pressure of L. infantum. Despite the CVL vaccine available on the market, the Brazilian Ministry of Health did not implement the use of it in their control programs. In this sense, there is an urgent need to develop more efficient vaccines. In this study, the association between two polymeric nanoformulations, [poly (D, L-lactic) acid (PLA) polymer] loading Leishmania amazonensis antigens, was evaluated as a potential immunobiological agent against VL using golden hamsters as an experimental model. The results indicated that no significant adverse reactions were observed in animals vaccinated with LAPSmP. LAPSmP presented similar levels of total anti-Leishmania IgG as compared to LAPSmG. The LAPSmP and LAPSmG groups showed an intense reduction in liver and spleen parasitic load by qPCR. The LAPSmP and LAPSmG vaccines showed exceptional results, indicating that they may be promising candidates as a VL vaccine.
ARTICLE | doi:10.20944/preprints202110.0117.v1
Online: 7 October 2021 (11:00:12 CEST)
Leishmanial skin lesions are characterized by inflammatory hypoxia alongside the activation of hypoxia inducible factors, HIF-1a and HIF-2a, and subsequent expression of the HIF-a target VEGF-A during Leishmania major infection. However, the factors responsible for HIF-a activation are not known. We hypothesize hypoxia and pro-inflammatory stimuli contribute to HIF-a activation during infection. RNASeq on leishmanial lesions found transcripts associated with HIF-1a signaling are induced. To determine whether hypoxia contributes to HIF-a activation, we followed the fate of myeloid cells infiltrating from the blood and into hypoxic lesions. Recruited myeloid cells experience hypoxia when they enter inflamed lesions, and the length of time in lesions increases their hypoxic signature. To determine whether pro-inflammatory stimuli in the inflamed tissue can also influence HIF-a activation, we subjected macrophages to various pro-inflammatory stimuli and measured VEGF-A. While parasites alone did not induce VEGF-A, and pro-inflammatory stimuli only modestly induce VEGF-A, HIF- stabilization increases VEGF-A during infection. HIF-a stabilization does not impact parasite entry, growth or killing. Alternatively, the absence of ARNT/HIF- signaling enhances parasite internalization. Altogether, these findings suggest HIF-a is active during infection, and while macrophage HIF-a activation promotes lymphatic remodeling through VEGF-A production, HIF-a activation does not impact parasite internalization or control.
ARTICLE | doi:10.20944/preprints202211.0376.v1
Subject: Chemistry, Medicinal Chemistry Keywords: synthesis; leishmaniasis; flavonoids; rCPB; molecular modelling.
Online: 21 November 2022 (06:29:51 CET)
Leishmaniasis is a neglected tropical disease and affects more than 350 million people worldwide. However, there are no vaccines for humans, and current treatment is hampered due to its high cost, numerous side effects, and painful administration routes. Ending its epidemics by 2030 has become a United Nations goal, and the multitarget drug strategy emerges as a promising alternative. Flavonoids are an example of multitarget compounds and organic synthesis represents a tool to obtain high yields of these molecules. In our study, we synthesized 17 flavonoid analogs using a scalable, easy-to-reproduce, and inexpensive method. All compounds demonstrated an impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y, which are highly expressed in the amastigote stage, the target form of the parasite. Compounds 3c, f12a, and f12b stood out as effective against all isoforms and intermolecular interactions were investigated through a molecular modeling study. The compounds were highly potent against the parasite and demonstrated low cytotoxic action against mammalian cells. The results were pioneering, representing an advance in the investigation of the mechanisms behind the antileishmanial action of flavonoid derivatives. Furthermore, compounds have shown to be promising leads for the design of other cysteine protease inhibitors for the treatment of leishmaniasis diseases.
BRIEF REPORT | doi:10.20944/preprints202211.0185.v1
Subject: Life Sciences, Microbiology Keywords: Leishmaniasis; drugs; parasites; ; herbal plants; treatments
Online: 10 November 2022 (06:44:40 CET)
Leishmaniasis is considered one of the different neglected tropical diseases by the World Health Organization. Over the past few decades to tackle leishmaniasis, effective and novel drugs have progressed. But few are expensive some other medication shows poor effects and few drugs with long treatment lead to cause resistance. But it is very important to start a better medication against leishmania so researchers came to the front of the utilization of natural products which are considered a better option. Finding active compounds in medicinal plants is another alternative to currently accessible medications. Materials and methods: This study examined and reported the far more potential natural products used to treat disease caused by Leishmania spp. Leishmaniasis, plant metabolites, in vivo, in vitro, and treatment against leishmaniasis have been used as search terms in the Google Scholar, PubMed, and Science Direct databases, and only papers published between 2015 and 2021 have been chosen for further analysis. Results: The use of novel natural compounds with leishmanicidal action as well as the leishmanicidal activity of natural compounds against promastigote, axenic, and intracellular amastigote forms were included in roughly 20 research papers that were reviewed.Conclusion: Due to their capacity to selectively target parasites without harming host cell viability, herbal plants are a possible source of new anti-leishmanial medication. Future leishmaniasis treatments will draw on the isolated compounds as a source, completing those already offered in clinics.
Subject: Medicine & Pharmacology, Allergology Keywords: visceral leishmaniasis; Kala Azar; Tanzania; East Africa
Online: 22 October 2020 (09:30:22 CEST)
Presentation of case: A 20 year old men from Simanjiro district in northern Tanzania presented with a 3 year history of splenomegaly, fatigue, cachexia, skin maculae and recent onset of watery diarrhea at Kilimanjaro Christian Medical Centre (KCMC) in Northern Tanzania. Due to laboratory findings of pancytopenia, diagnostic workup included bone marrow aspiration cytology and biopsy. Although the rapid test (IT LEISH, rK39 RDT) was negative, blood smear showed amastigote forms of Leishmaniasis in macrophages. Repeat bone marrow aspiration and PCR eventually confirmed VL. The patient denied travel to known endemic areas of visceral leishmaniasis (VL). Treatment was initiated with Amphotericin B, but the patient died on the fourth day of treatment from respiratory insufficiency. An autopsy revealed massive organ manifestations of VL. Case discussion: This is the first reported autochthonous case of VL in Tanzania. Clark et al. detected the vector Phlebotomous martini in Northern Tanzania in 2013, in a region boardering the district of our patient. The negative rapid test draws attention to the fact that sensitivity and specificity was found to be low in East African VL patients as displayed earlier by a Kenyan study. Therefore, tissue samples (spleen or bone marrow) remain necessary for diagnosis. The variety of symptoms in this presented case was remarkable, including the occurrence of Post Kala Azar Dermal Leishmaniasis (PKDL) and VL at the same time. This has been described in East African VL cases before as well as the occurrence of chronic diarrhea. An elongated undiagnosed period likely led to a mixed clinical picture that included: hepato-splenomegaly, PKDL, cachexia, and diarrhea.
REVIEW | doi:10.20944/preprints201902.0122.v4
Subject: Life Sciences, Biophysics Keywords: Leishmania; leishmaniasis; Theoretical Physics and Chimistry; Molecular Dynamics
Online: 1 March 2022 (12:58:34 CET)
We report on the state of the art of research on proteins recognized as potential targets for the development of Leishmania treatments and the search of active chemical species. We have reviewed information from experimental in vitro, in vivo, or in silico sources. We classify the gathered information on: a) vector taxonomy and geographical distribution, b) parasite taxonomy, geographical distribution, c) enzymatic function of proteins related to the parasite/host in any of its development states, id. est., oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases and cytokines, and d) information on standard and non-standard treatments from bioactive chemical species. Our aim is to provide a much needed reference layout for research efforts aimed to understand the interaction mechanisms of ligand-protein activation/inactivation processes, specifically related to Leishmania, thus, we focus on enzymes known to be part of the biochemical molecular pathways initiated following a Leishmania infectious episode.
REVIEW | doi:10.20944/preprints201911.0337.v1
Subject: Biology, Other Keywords: leishmania; visceral leishmaniasis; Americas; genome instability,; fitness gain
Online: 27 November 2019 (09:27:16 CET)
Pathogen fitness landscapes change when transmission cycles establish in non-native environments or spill over into new vectors and hosts. The introduction of Leishmania infantum in the Americas into the Neotropics during European colonization represents a unique case study to investigate mechanisms of ecological adaptation of this important parasite. Defining the evolutionary trajectories that drive L. infantum fitness in this new environment are of great public health importance as they will allow unique insight into pathways of host/pathogen co-evolution and their consequences for region-specific changes in disease manifestation. This review summarizes current knowledge on L. infantum genetic and phenotypic diversity in the Americas and its possible role in the unique epidemiology of VL in the New World. We highlight the importance of appreciating adaptive molecular mechanisms in L. infantum to understand the parasites’ successful establishment on the continent.
ARTICLE | doi:10.20944/preprints201703.0065.v1
Subject: Social Sciences, Econometrics & Statistics Keywords: generalized estimating equations; overdispersion; poisson; spatio-temporal; Leishmaniasis
Online: 13 March 2017 (09:30:11 CET)
This paper is motivated by spatio-temporal pattern in the occurrence of Leishmaniasis in Afghanistan and the relatively high number of zero counts. We hold the view that correlations that arise from spatial and temporal sources are inherently distinct. Our method decouples these two sources of correlations, there are at least two advantages in taking this approach. First, it circumvents the need to inverting a large correlation matrix, which is a commonly encountered problem in spatio-temporal analyses. Second, it simplifies the modelling of complex relationships such as anisotropy, which would have been extremely difficult or impossible if spatio-temporal correlations were simultaneously considered. We identify three challenges in the modelling of a spatio-temporal process: (1) accommodation of covariances that arise from spatial and temporal sources; (2) choosing the correct covariance structure and (3) extending to situations where a covariance is not the natural measure of association. Moreover, because the data covers a period that overlaps with the US invasion of Afghanistan, the high number of zero counts may be the result of no disease incidence or lapse of data collection. To resolve this issue, a model truncated at zero built on a foundation of the generalized estimating equations was proposed.
ARTICLE | doi:10.20944/preprints201801.0292.v1
Subject: Chemistry, Medicinal Chemistry Keywords: African medicinal plants; Leishmaniasis; natural products; protozoal diseases; Schistosomiasis; Trypanosomiasis
Online: 31 January 2018 (05:28:15 CET)
Parasitic diseases continue represent a threat on a global scale, particularly among the poorest countries in the world. This is particularly because of the absence of vaccines, and in some cases, resistance against available drugs, currently being used for their treatment. In this review emphasis is laid on natural products and scaffolds from African medicinal plants (AMPs) for lead drug discovery and possible further development of drugs for the treatment of parasitic diseases. In the discussion, emphasis has been laid on alkaloids, terpenoids, quinones, flavonoids and narrower compound classes of compounds with micromolar range activities against Schistosoma, Trypanosoma and Leishmania species. Suggestions for future drug development from African medicinal plants have also been provided.
ARTICLE | doi:10.20944/preprints201609.0098.v1
Subject: Mathematics & Computer Science, Other Keywords: ecological niche model; environment; overdispersion; negative binomial; leishmaniasis; infectious disease
Online: 27 September 2016 (10:17:31 CEST)
Leishmaniasis is the third most common vector-borne disease and a very important protozoan infection. Cutaneous leishmaniasis is one of the most common types of leishmaniasis infectious diseases with up to 2 million occurrences of new cases each year worldwide. A dynamic transmission multivariate time series model was applied to the data to account for overdispersion and evaluate the effects of three environmental layers as well as seasonality in the data. Furthermore, ecological niche modeling was used to investigate the geographical suitable conditions for cutaneous leishmaniasis using temperature, precipitation and altitude as environmental layers, together with the leishmaniasis presence data. A retrospective analysis of the cutaneous leishmaniasis spatial data in Afghanistan between 2003 and 2009 indicates a steady increase from 2003 to 2007, a small decrease in 2008, then another increase in 2009. An upward trend and regularly repeating patterns of highs and lows was observed related to the months of the year which suggests seasonality effect in the data. Two peaks were observed in the disease occurrence-- January to March and September to December -- which coincide with the cold period. Ecological niche modelling indicates that precipitation has the greatest contribution to the potential distribution of leishmaniasis.