scholarly journals Can We Harness Immune Responses to Improve Drug Treatment in Leishmaniasis?

2020 ◽  
Vol 8 (7) ◽  
pp. 1069
Author(s):  
Raphael Taiwo Aruleba ◽  
Katharine C. Carter ◽  
Frank Brombacher ◽  
Ramona Hurdayal
Keyword(s):  
Immune Responses ◽  
Economic Status ◽  
Clinical Manifestations ◽  
Steady Increase ◽  
Clinical Use ◽  
Self Healing ◽  
Cutaneous Lesions ◽  
Vector Borne ◽  
Visceral Disease ◽  
Control And Eradication

Leishmaniasis is a vector-borne parasitic disease that has been neglected in priority for control and eradication of malaria, tuberculosis, and HIV/AIDS. Collectively, over one seventh of the world’s population is at risk of being infected with 0.7–1.2 million new infections reported annually. Clinical manifestations range from self-healing cutaneous lesions to fatal visceral disease. The first anti-leishmanial drugs were introduced in the 1950′s and, despite several shortcomings, remain the mainstay for treatment. Regardless of this and the steady increase in infections over the years, particularly among populations of low economic status, research on leishmaniasis remains under funded. This review looks at the drugs currently in clinical use and how they interact with the host immune response. Employing chemoimmunotherapeutic approaches may be one viable alternative to improve the efficacy of novel/existing drugs and extend their lifespan in clinical use.

scholarly journals Analyses of Leishmania-LRV Co-Phylogenetic Patterns and Evolutionary Variability of Viral Proteins

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2305
Author(s):  
Alexei Y. Kostygov ◽  
Danyil Grybchuk ◽  
Yulia Kleschenko ◽  
Daniil S. Chistyakov ◽  
Alexander N. Lukashev ◽  
...  
Keyword(s):  
Rna Virus ◽  
Clinical Manifestations ◽  
Purifying Selection ◽  
Viral Proteins ◽  
Small Scale ◽  
Self Healing ◽  
Genes Encoding ◽  
Leishmania Spp ◽  
Life Threatening ◽  
Vector Borne

Leishmania spp. are important pathogens causing a vector-borne disease with a broad range of clinical manifestations from self-healing ulcers to the life-threatening visceral forms. Presence of Leishmania RNA virus (LRV) confers survival advantage to these parasites by suppressing anti-leishmanial immunity in the vertebrate host. The two viral species, LRV1 and LRV2 infect species of the subgenera Viannia and Leishmania, respectively. In this work we investigated co-phylogenetic patterns of leishmaniae and their viruses on a small scale (LRV2 in L. major) and demonstrated their predominant coevolution, occasionally broken by intraspecific host switches. Our analysis of the two viral genes, encoding the capsid and RNA-dependent RNA polymerase (RDRP), revealed them to be under the pressure of purifying selection, which was considerably stronger for the former gene across the whole tree. The selective pressure also differs between the LRV clades and correlates with the frequency of interspecific host switches. In addition, using experimental (capsid) and predicted (RDRP) models we demonstrated that the evolutionary variability across the structure is strikingly different in these two viral proteins.

scholarly journals One Health Approach to Leishmaniases: Understanding the Disease Dynamics through Diagnostic Tools

Pathogens ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 809 ◽  
Author(s):  
Ahyun Hong ◽  
Ricardo Andrade Zampieri ◽  
Jeffrey Jon Shaw ◽  
Lucile Maria Floeter-Winter ◽  
Maria Fernanda Laranjeira-Silva
Keyword(s):  
One Health ◽  
Environmental Changes ◽  
Clinical Manifestations ◽  
Control Measures ◽  
Sand Fly ◽  
Diagnostic Tools ◽  
Self Healing ◽  
Animal Reservoir ◽  
Vector Borne Diseases ◽  
Vector Borne

Leishmaniases are zoonotic vector-borne diseases caused by protozoan parasites of the genus Leishmania that affect millions of people around the globe. There are various clinical manifestations, ranging from self-healing cutaneous lesions to potentially fatal visceral leishmaniasis, all of which are associated with different Leishmania species. Transmission of these parasites is complex due to the varying ecological relationships between human and/or animal reservoir hosts, parasites, and sand fly vectors. Moreover, vector-borne diseases like leishmaniases are intricately linked to environmental changes and socioeconomic risk factors, advocating the importance of the One Health approach to control these diseases. The development of an accurate, fast, and cost-effective diagnostic tool for leishmaniases is a priority, and the implementation of various control measures such as animal sentinel surveillance systems is needed to better detect, prevent, and respond to the (re-)emergence of leishmaniases.

scholarly journals Protective or Detrimental? Understanding the Role of Host Immunity in Leishmaniasis

2019 ◽  
Vol 7 (12) ◽  
pp. 695 ◽  
Author(s):  
Camila dos Santos Meira ◽  
Lashitew Gedamu
Keyword(s):  
Immune Cells ◽  
Rna Virus ◽  
Clinical Manifestations ◽  
Host Immunity ◽  
Host Cells ◽  
Health Concern ◽  
Insect Vector ◽  
Self Healing ◽  
Cutaneous Lesions ◽  
Adaptive Immune Cells

The intracellular protozoan parasites of the genus Leishmania are the causative agents of leishmaniasis, a vector-borne disease of major public health concern, estimated to affect 12 million people worldwide. The clinical manifestations of leishmaniasis are highly variable and can range from self-healing localized cutaneous lesions to life-threatening disseminated visceral disease. Once introduced into the skin by infected sandflies, Leishmania parasites interact with a variety of immune cells, such as neutrophils, monocytes, dendritic cells (DCs), and macrophages. The resolution of infection requires a finely tuned interplay between innate and adaptive immune cells, culminating with the activation of microbicidal functions and parasite clearance within host cells. However, several factors derived from the host, insect vector, and Leishmania spp., including the presence of a double-stranded RNA virus (LRV), can modulate the host immunity and influence the disease outcome. In this review, we discuss the immune mechanisms underlying the main forms of leishmaniasis, some of the factors involved with the establishment of infection and disease severity, and potential approaches for vaccine and drug development focused on host immunity.

scholarly journals Thermoresponsive Copolymer Nanovectors Improve the Bioavailability of Retrograde Inhibitors in the Treatment of Leishmania Infections

2021 ◽  
Vol 11 ◽  
Author(s):  
Evan Craig ◽  
Anna Calarco ◽  
Raffaele Conte ◽  
Veronica Ambrogi ◽  
Giovanna Gomez d’Ayala ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
Mass Spectrometry Analysis ◽  
Self Healing ◽  
Cutaneous Lesions ◽  
Spectrometry Analysis ◽  
Nanoparticle Aggregates ◽  
Hydrophobic Molecule ◽  
Infected Cells ◽  
Viable Approach ◽  
Drug Resistant Strains

Clinical manifestations of leishmaniasis range from self-healing, cutaneous lesions to fatal infections of the viscera. With no preventative Leishmania vaccine available, the frontline option against leishmaniasis is chemotherapy. Unfortunately, currently available anti-Leishmania drugs face several obstacles, including toxicity that limits dosing and emergent drug resistant strains in endemic regions. It is, therefore, imperative that more effective drug formulations with decreased toxicity profiles are developed. Previous studies had shown that 2-(((5-Methyl-2-thienyl)methylene)amino)-N-phenylbenzamide (also called Retro-2) has efficacy against Leishmania infections. Structure–activity relationship (SAR) analogs of Retro-2, using the dihydroquinazolinone (DHQZ) base structure, were subsequently described that are more efficacious than Retro-2. However, considering the hydrophobic nature of these compounds that limits their solubility and uptake, the current studies were initiated to determine whether the solubility of Retro-2 and its SAR analogs could be enhanced through encapsulation in amphiphilic polymer nanoparticles. We evaluated encapsulation of these compounds in the amphiphilic, thermoresponsive oligo(ethylene glycol) methacrylate-co-pentafluorostyrene (PFG30) copolymer that forms nanoparticle aggregates upon heating past temperatures of 30°C. The hydrophobic tracer, coumarin 6, was used to evaluate uptake of a hydrophobic molecule into PFG30 aggregates. Mass spectrometry analysis showed considerably greater delivery of encapsulated DHQZ analogs into infected cells and more rapid shrinkage of L. amazonensis communal vacuoles. Moreover, encapsulation in PFG30 augmented the efficacy of Retro-2 and its SAR analogs to clear both L. amazonensis and L. donovani infections. These studies demonstrate that encapsulation of compounds in PFG30 is a viable approach to dramatically increase bioavailability and efficacy of anti-Leishmania compounds.

scholarly journals A Disease Control-Oriented Land Cover Land Use Map for Myanmar

Data ◽  
2021 ◽  
Vol 6 (6) ◽  
pp. 63
Author(s):  
Dong Chen ◽  
Varada Shevade ◽  
Allison Baer ◽  
Jiaying He ◽  
Amanda Hoffman-Hall ◽  
...  
Keyword(s):  
Remote Sensing ◽  
Land Use ◽  
Land Cover ◽  
Population Distribution ◽  
Large Spatial Scale ◽  
The Public ◽  
Spatial Coverage ◽  
Vector Borne ◽  
Do So ◽  
Control And Eradication

Malaria is a serious infectious disease that leads to massive casualties globally. Myanmar is a key battleground for the global fight against malaria because it is where the emergence of drug-resistant malaria parasites has been documented. Controlling the spread of malaria in Myanmar thus carries global significance, because the failure to do so would lead to devastating consequences in vast areas where malaria is prevalent in tropical/subtropical regions around the world. Thanks to its wide and consistent spatial coverage, remote sensing has become increasingly used in the public health domain. Specifically, remote sensing-based land cover/land use (LCLU) maps present a powerful tool that provides critical information on population distribution and on the potential human-vector interactions interfaces on a large spatial scale. Here, we present a 30-meter LCLU map that was created specifically for the malaria control and eradication efforts in Myanmar. This bottom-up approach can be modified and customized to other vector-borne infectious diseases in Myanmar or other Southeastern Asian countries.

scholarly journals The Potency of Seaweed Sulfated Polysaccharides for the Correction of Hemostasis Disorders in COVID-19

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2618
Author(s):  
Tatyana A. Kuznetsova ◽  
Boris G. Andryukov ◽  
Ilona D. Makarenkova ◽  
Tatyana S. Zaporozhets ◽  
Natalya N. Besednova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Therapeutic Potential ◽  
Low Cost ◽  
Clinical Manifestations ◽  
Optimal Dose ◽  
Monosaccharide Composition ◽  
Structural Features ◽  
Sulfated Polysaccharides ◽  
Clinical Use ◽  
Hemostasis System

Hemostasis disorders play an important role in the pathogenesis, clinical manifestations, and outcome of COVID-19. First of all, the hemostasis system suffers due to a complicated and severe course of COVID-19. A significant number of COVID-19 patients develop signs of hypercoagulability, thrombocytopenia, and hyperfibrinolysis. Patients with severe COVID-19 have a tendency toward thrombotic complications in the venous and arterial systems, which is the leading cause of death in this disease. Despite the success achieved in the treatment of SARS-CoV-2, the search for new effective anticoagulants, thrombolytics, and fibrinolytics, as well as their optimal dose strategies, continues to be relevant. The wide therapeutic potential of seaweed sulfated polysaccharides (PSs), including anticoagulant, thrombolytic, and fibrinolytic activities, opens up new possibilities for their study in experimental and clinical trials. These natural compounds can be important complementary drugs for the recovery from hemostasis disorders due to their natural origin, safety, and low cost compared to synthetic drugs. In this review, the authors analyze possible pathophysiological mechanisms involved in the hemostasis disorders observed in the pathological progression of COVID-19, and also focus the attention of researchers on seaweed PSs as potential drugs aimed to correction these disorders in COVID-19 patients. Modern literature data on the anticoagulant, antithrombotic, and fibrinolytic activities of seaweed PSs are presented, depending on their structural features (content and position of sulfate groups on the main chain of PSs, molecular weight, monosaccharide composition and type of glycosidic bonds, the degree of PS chain branching, etc.). The mechanisms of PS action on the hemostasis system and the issues of oral bioavailability of PSs, important for their clinical use as oral anticoagulant and antithrombotic agents, are considered. The combination of the anticoagulant, thrombolytic, and fibrinolytic properties, along with low toxicity and relative cheapness of production, open up prospects for the clinical use of PSs as alternative sources of new anticoagulant and antithrombotic compounds. However, further investigation and clinical trials are needed to confirm their efficacy.

scholarly journals STUDIES ON THE ETIOLOGY OF RABBIT POX

1936 ◽  
Vol 63 (3) ◽  
pp. 353-378 ◽  
Author(s):  
Ch'uan-K'uei Hu ◽  
Paul D. Rosahn ◽  
Louise Pearce
Keyword(s):  
New York ◽  
Clinical Manifestations ◽  
Vaccine Virus ◽  
Intradermal Injection ◽  
Skin Area ◽  
Cutaneous Lesions ◽  
Active Growth ◽  
Specific Relationship ◽  
Close Relationship ◽  
The One

Experiments are reported in which it was shown that rabbits which had recovered from experimental or spontaneous rabbit pox were refractory to inoculation of pox virus injected by various routes, and in addition did not develop clinical manifestations of the disease under conditions of exposure to florid cases of pox. It was found that pox recovered rabbits were susceptible to inoculation with the virus of virus III disease of rabbits and that virus III recovered rabbits could be successfully inoculated with pox virus. Furthermore, virus III recovered rabbits developed pox when subjected to room exposure in the same manner as did normal rabbits. It thus appears that there is no specific relationship between the two viruses. Rabbits which had recovered from experimental or spontaneous pox were found to be just as susceptible to inoculation with the virus of infectious myxoma of rabbits as were normal rabbits, a result which demonstrates that there is no specific relationship between these viruses. Rabbits which had recovered from experimental or spontaneous pox were refractory to inoculation with culture dermovaccine virus, but vaccine recovered rabbits were not completely refractory to inoculation with pox virus. Under conditions of exposure to clinical cases of pox, adult vaccine immune rabbits did not develop clinical manifestations of pox, but young, recently weaned vaccinated rabbits did contract mild but definite clinical pox. Experimental pox recovered rabbits were partially refractory to inoculation with neurovaccine virus and neurovaccine recovered rabbits were partially refractory to inoculation with pox virus. The refractory condition of the pox immune rabbits appeared to be more pronounced than that of the neurovaccine immunes. The cutaneous lesions which developed from the intradermal injection of pox, neurovaccine, and culture vaccine viruses showed definite differences with respect to the rate and persistence of active growth, amount of edema, hemorrhage, and necrosis, and the degree of tissue destructiveness. These features were most pronounced in the lesions of pox virus and were least marked in the lesions of culture vaccine virus. The differences were particularly apparent in normal rabbits, but they were also present in the lesions which developed in immune animals. It was found that the calf was susceptible to inoculation with pox virus applied to a scarified skin area. There were many similarities in the appearance and course of the pox lesions to those resulting from culture vaccine virus, the New York Board of Health vaccine, and neurovaccine virus similarly inoculated. But the pox lesions were most numerous, much the largest and most destructive, and by far the most persistent while next in order were those of the Board of Health dermovaccine. The results of these various experiments showed that a close relationship obtains between pox virus, on the one hand, and vaccine virus and neurovaccine virus, on the other, but it cannot be said that pox virus is identical in all respects with either one of these viruses. The findings indicated that the relationship between pox and neurovaccine viruses is closer than that between pox and culture vaccine viruses. Upon the basis of the results observed in culture (dermo) vaccine immune rabbits inoculated with or exposed to pox, it appeared that vaccination with vaccine virus offered a method of protection against rabbit pox.

Influence of Obesity on Clinical Manifestations and Response to Therapy in Cutaneous Leishmaniasis caused by Leishmania braziliensis

2021 ◽  
Author(s):  
Tainã Lago ◽  
Lucas Carvalho ◽  
Mauricio Nascimento ◽  
Luiz H Guimarães ◽  
Jamile Lago ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Clinical Presentation ◽  
Clinical Manifestations ◽  
Healing Time ◽  
Response To Therapy ◽  
Leishmania Braziliensis ◽  
Cutaneous Lesions ◽  
Cytokine Levels ◽  
Cure Rates ◽  
The Impact

Abstract Background Cutaneous leishmaniasis (CL) caused by L. braziliensis is characterized by a single ulcer or multiple cutaneous lesions with raised borders. Cure rates below 60% are observed in response to meglumine antimoniate therapy. We investigated the impact of obesity on CL clinical presentation and therapeutic response. Methods A total of 90 age-matched CL patients were included (30 obese, 30 overweight and 30 with normal BMI). CL was diagnosed through documentation of L. braziliensis DNA by PCR or identification of amastigotes in biopsied skin lesion samples. Serum cytokine levels were determined by chemiluminescence. Antimony therapy with Glucantime (20mg/kg/day) was administered for 20 days. Results Obese CL patients may present hypertrophic ulcers rather than typical oval, ulcerated lesions. A direct correlation between BMI and healing time was noted. After one course of Antimony, cure was achieved in 73% of patients with normal BMI, 37% of overweight subjects, yet just 18% of obese CL patients (p<0.01). Obese CL cases additionally presented higher leptin levels than overweight patients or those with normal BMI (p<0.05). Conclusions Obesity modifies the clinical presentation of CL and host immune response, and is associated with greater failure to therapy.

N-Acetyl Galactosamine Targeting: Paving the Way for Clinical Application of Nucleotide Medicines in Cardiovascular Diseases

2021 ◽  
Author(s):  
Erik A.L. Biessen ◽  
Theo J.C. Van Berkel
Keyword(s):  
Immune Responses ◽  
Targeted Delivery ◽  
Antisense Oligonucleotides ◽  
Sugar Metabolism ◽  
Innate Immune ◽  
Future Research ◽  
Clinical Use ◽  
Innate Immune Responses ◽  
Chemically Modified ◽  
Intrinsic Capacity

While the promise of oligonucleotide therapeutics, such as (chemically modified) ASO (antisense oligonucleotides) and short interfering RNAs, is undisputed from their introduction onwards, their unfavorable pharmacokinetics and intrinsic capacity to mobilize innate immune responses, were limiting widespread clinical use. However, these major setbacks have been tackled by breakthroughs in chemistry, stability and delivery. When aiming an intervention hepatic targets, such as lipid and sugar metabolism, coagulation, not to mention cancer and virus infection, introduction of N-acetylgalactosamine aided targeting technology has advanced the field profoundly and by now a dozen of N-acetylgalactosamine therapeutics for these indications have been approved for clinical use or have progressed to clinical trial stage 2 to 3 testing. This technology, in combination with major advances in oligonucleotide stability allows safe and durable intervention in targets that were previously deemed undruggable, such as Lp(a) and PCSK9, at high efficacy and specificity, often with as little as 2 doses per year. Their successful use even the most visionary would not have predicted 2 decades ago. Here, we will review the evolution of N-acetylgalactosamine technology. We shall outline their fundamental design principles and merits, and their application for the delivery of oligonucleotide therapeutics to the liver. Finally, we will discuss the perspectives of N-acetylgalactosamine technology and propose directions for future research in receptor targeted delivery of these gene medicines.

scholarly journals Spatial metabolomics identifies localized chemical changes in heart tissue during chronic cardiac Chagas Disease

2021 ◽  
Vol 15 (10) ◽  
pp. e0009819
Author(s):  
Danya A. Dean ◽  
Gautham Gautham ◽  
Jair L. Siqueira-Neto ◽  
James H. McKerrow ◽  
Pieter C. Dorrestein ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Neglected Tropical Diseases ◽  
Clinical Manifestations ◽  
Parasite Burden ◽  
Heart Tissue ◽  
Cardiac Symptoms ◽  
Heart Region ◽  
Contaminated Food ◽  
Vector Borne ◽  
Insight Into

Chagas disease (CD), caused by the parasite Trypanosoma cruzi, is one of nineteen neglected tropical diseases. CD is a vector-borne disease transmitted by triatomines, but CD can also be transmitted through blood transfusions, organ transplants, T. cruzi-contaminated food and drinks, and congenital transmission. While endemic to the Americas, T. cruzi infects 7–8 million people worldwide and can induce severe cardiac symptoms including apical aneurysms, thromboembolisms and arrhythmias during the chronic stage of CD. However, these cardiac clinical manifestations and CD pathogenesis are not fully understood. Using spatial metabolomics (chemical cartography), we sought to understand the localized impact of chronic CD on the cardiac metabolome of mice infected with two divergent T. cruzi strains. Our data showed chemical differences in localized cardiac regions upon chronic T. cruzi infection, indicating that parasite infection changes the host metabolome at specific sites in chronic CD. These sites were distinct from the sites of highest parasite burden. In addition, we identified acylcarnitines and glycerophosphocholines as discriminatory chemical families within each heart region, comparing infected and uninfected samples. Overall, our study indicated global and positional metabolic differences common to infection with different T. cruzi strains and identified select infection-modulated pathways. These results provide further insight into CD pathogenesis and demonstrate the advantage of a systematic spatial perspective to understand infectious disease tropism.

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