A Multifaceted Approach to Combating Leishmaniasis, a Neglected Tropical Disease
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Five Facts About Giardia Lamblia
PEARLS Five facts about Giardia lamblia Lenka Cernikova, Carmen FasoID, Adrian B. HehlID* Laboratory of Molecular Parasitology, Institute of Parasitology, University of Zurich (ZH), Zurich, Switzerland * [email protected] Fact 1: Infection with Giardia lamblia is one of the most common causes of waterborne nonbacterial and nonviral diarrheal disease G. lamblia (syn. intestinalis, duodenalis) is a zoonotic enteroparasite. It proliferates in an extra- cellular and noninvasive fashion in the small intestine of vertebrate hosts, causing the diarrheal disease known as giardiasis. Virtually all mammals can be infected with G. lamblia, and epide- miological data point to giardiasis as a zoonosis [1]. Infections in humans may be asymptom- atic or associated with diarrhea, malabsorption, bloating, abdominal pain, fatigue, and weight loss. Based on the latest figures provided by WHO, G. lamblia is the third most common agent of diarrheal disease worldwide with over 300 million reported cases per annum, preceded only a1111111111 by rotavirus and Cryptosporidium parvum and hominis in the most vulnerable target group of a1111111111 a1111111111 children under five years of age [2]. The prevalence of giardiasis in humans ranges from 2%± a1111111111 3% in industrialized countries, up to 30% in low-income and developing countries [3]. Giardi- a1111111111 asis was formerly included in the WHO neglected diseases initiative and is directly associated with poverty and poor quality of drinking water [4]. Acute infection develops over a period of three weeks, peaking at eight days post infection. Generally, healthy hosts clear the infection within 2±3 weeks, whereas the occasional chronically infected host shows signs of villus and crypt atrophy, enterocyte apoptosis, and ultimately severe disruption of epithelial barrier func- OPEN ACCESS tion [5]. -
In Vitro Screening for Inhibitors of the Human Mitotic Kinesin Eg5 with Antimitotic and Antitumor Activities
Molecular Cancer Therapeutics 1079 In vitro screening for inhibitors of the human mitotic kinesin Eg5 with antimitotic and antitumor activities Salvatore DeBonis,1 Dimitrios A. Skoufias,1 agents were mainly first isolated from plants. The Vinca Luc Lebeau,2 Roman Lopez,3 Gautier Robin,1 alkaloids, vincristine and vinblastine (isolated from leaves Robert L. Margolis,1 Richard H. Wade,1 of the Madagascar periwinkle plant), are now used to treat and Frank Kozielski1 leukemia and Hodgkin’s lymphoma, whereas paclitaxel 1 2 (Taxol) [originally extracted from the bark of the western Institut de Biologie Structurale, Grenoble, France; Laboratoire yew tree (2)] and its semisynthetic analogue docetaxel de Chimie Organique Applique´e, Centre National de la Recherche Scientifique, Universite´Louis Pasteur, Faculte´de Pharmacie, (Taxotere) are approved for the treatment of metastatic Illkirch, France; and 3Service de Marquage Mole´culaire et de breast and ovarian carcinomas. The success of these natural Chimie Bio-organique, CEA-Saclay, Gif sur Yvette, France products has initiated the development of f30 second- generation tubulin drugs currently in preclinical or clinical development (reviewed in ref. 3). Abstract All antimitotic tubulin agents interfere with the assembly Human Eg5, a member of the kinesin superfamily, plays and/or disassembly of microtubules and produce a char- a key role in mitosis, as it is required for the formation of acteristic mitotic arrest phenotype. Even low paclitaxel a bipolar spindle. We describe here the first in vitro concentrations (f10 nmol/L), with no obvious effect on microtubule-activated ATPase-based assay for the identi- microtubule dynamics, are sufficient to block cells in mito- fication of small-molecule inhibitors of Eg5. -
Giardiasis Importance Giardiasis, a Gastrointestinal Disease Characterized by Acute Or Chronic Diarrhea, Is Caused by Protozoan Parasites in the Genus Giardia
Giardiasis Importance Giardiasis, a gastrointestinal disease characterized by acute or chronic diarrhea, is caused by protozoan parasites in the genus Giardia. Giardia duodenalis is the major Giardia Enteritis, species found in mammals, and the only species known to cause illness in humans. This Lambliasis, organism is carried in the intestinal tract of many animals and people, with clinical signs Beaver Fever developing in some individuals, but many others remaining asymptomatic. In addition to diarrhea, the presence of G. duodenalis can result in malabsorption; some studies have implicated this organism in decreased growth in some infected children and Last Updated: December 2012 possibly decreased productivity in young livestock. Outbreaks are occasionally reported in people, as the result of mass exposure to contaminated water or food, or direct contact with infected individuals (e.g., in child care centers). People are considered to be the most important reservoir hosts for human giardiasis. The predominant genetic types of G. duodenalis usually differ in humans and domesticated animals (livestock and pets), and zoonotic transmission is currently thought to be of minor significance in causing human illness. Nevertheless, there is evidence that certain isolates may sometimes be shared, and some genetic types of G. duodenalis (assemblages A and B) should be considered potentially zoonotic. Etiology The protozoan genus Giardia (Family Giardiidae, order Giardiida) contains at least six species that infect animals and/or humans. In most mammals, giardiasis is caused by Giardia duodenalis, which is also called G. intestinalis. Both names are in current use, although the validity of the name G. intestinalis depends on the interpretation of the International Code of Zoological Nomenclature. -
Supplementary Information
Supplementary Information Network-based Drug Repurposing for Novel Coronavirus 2019-nCoV Yadi Zhou1,#, Yuan Hou1,#, Jiayu Shen1, Yin Huang1, William Martin1, Feixiong Cheng1-3,* 1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA 2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA 3Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA #Equal contribution *Correspondence to: Feixiong Cheng, PhD Lerner Research Institute Cleveland Clinic Tel: +1-216-444-7654; Fax: +1-216-636-0009 Email: [email protected] Supplementary Table S1. Genome information of 15 coronaviruses used for phylogenetic analyses. Supplementary Table S2. Protein sequence identities across 5 protein regions in 15 coronaviruses. Supplementary Table S3. HCoV-associated host proteins with references. Supplementary Table S4. Repurposable drugs predicted by network-based approaches. Supplementary Table S5. Network proximity results for 2,938 drugs against pan-human coronavirus (CoV) and individual CoVs. Supplementary Table S6. Network-predicted drug combinations for all the drug pairs from the top 16 high-confidence repurposable drugs. 1 Supplementary Table S1. Genome information of 15 coronaviruses used for phylogenetic analyses. GenBank ID Coronavirus Identity % Host Location discovered MN908947 2019-nCoV[Wuhan-Hu-1] 100 Human China MN938384 2019-nCoV[HKU-SZ-002a] 99.99 Human China MN975262 -
Leishmaniasis in the United States: Emerging Issues in a Region of Low Endemicity
microorganisms Review Leishmaniasis in the United States: Emerging Issues in a Region of Low Endemicity John M. Curtin 1,2,* and Naomi E. Aronson 2 1 Infectious Diseases Service, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA 2 Infectious Diseases Division, Uniformed Services University, Bethesda, MD 20814, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-011-301-295-6400 Abstract: Leishmaniasis, a chronic and persistent intracellular protozoal infection caused by many different species within the genus Leishmania, is an unfamiliar disease to most North American providers. Clinical presentations may include asymptomatic and symptomatic visceral leishmaniasis (so-called Kala-azar), as well as cutaneous or mucosal disease. Although cutaneous leishmaniasis (caused by Leishmania mexicana in the United States) is endemic in some southwest states, other causes for concern include reactivation of imported visceral leishmaniasis remotely in time from the initial infection, and the possible long-term complications of chronic inflammation from asymptomatic infection. Climate change, the identification of competent vectors and reservoirs, a highly mobile populace, significant population groups with proven exposure history, HIV, and widespread use of immunosuppressive medications and organ transplant all create the potential for increased frequency of leishmaniasis in the U.S. Together, these factors could contribute to leishmaniasis emerging as a health threat in the U.S., including the possibility of sustained autochthonous spread of newly introduced visceral disease. We summarize recent data examining the epidemiology and major risk factors for acquisition of cutaneous and visceral leishmaniasis, with a special focus on Citation: Curtin, J.M.; Aronson, N.E. -
Leishmania Major Is Not Altered by in Vitro Exposure to 2,3,7,8‑Tetrachlorodibenzo‑P‑Dioxin Vera Sazhnev and Gregory K
Sazhnev and DeKrey BMC Res Notes (2018) 11:642 https://doi.org/10.1186/s13104-018-3759-x BMC Research Notes RESEARCH NOTE Open Access The growth and infectivity of Leishmania major is not altered by in vitro exposure to 2,3,7,8‑tetrachlorodibenzo‑p‑dioxin Vera Sazhnev and Gregory K. DeKrey* Abstract Objective: The numbers of Leishmania major parasites in foot lesions of C57Bl/6, BALB/c or SCID mice can be signif- cantly reduced by pre-exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). One potential mechanism to explain this enhanced resistance to infection is that TCDD is directly toxic to L. major. This potential mechanism was addressed by exposing L. major promastigotes and amastigotes to TCDD in vitro and examining their subsequent proliferation and infectivity. Results: We found no signifcant change in the rate of in vitro L. major proliferation (promastigotes or amastigotes) after TCDD exposure at concentrations up to 100 nM. Moreover, in vitro TCDD exposure did not signifcantly alter the ability of L. major to infect mice, trigger lesion formation, or survive in those lesions. Keywords: Leishmania major, Dioxin, TCDD, Proliferation, Infectivity Introduction Previous studies in this laboratory have found that the Approximately one million new cases of leishmaniasis numbers of L. major parasites in foot lesions of C57Bl/6, occur each year worldwide [1, 2]. Of the various forms, BALB/c or SCID mice can be signifcantly reduced by cutaneous leishmaniasis is the most common, and vis- exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) ceral leishmaniasis is the most deadly. -
The Cytoskeleton of Giardia Lamblia
International Journal for Parasitology 33 (2003) 3–28 www.parasitology-online.com Invited review The cytoskeleton of Giardia lamblia Heidi G. Elmendorfa,*, Scott C. Dawsonb, J. Michael McCafferyc aDepartment of Biology, Georgetown University, 348 Reiss Building 37th and O Sts. NW, Washington, DC 20057, USA bDepartment of Molecular and Cell Biology, University of California Berkeley, 345 LSA Building, Berkeley, CA 94720, USA cDepartment of Biology, Johns Hopkins University, Integrated Imaging Center, Baltimore, MD 21218, USA Received 18 July 2002; received in revised form 18 September 2002; accepted 19 September 2002 Abstract Giardia lamblia is a ubiquitous intestinal pathogen of mammals. Evolutionary studies have also defined it as a member of one of the earliest diverging eukaryotic lineages that we are able to cultivate and study in the laboratory. Despite early recognition of its striking structure resembling a half pear endowed with eight flagella and a unique ventral disk, a molecular understanding of the cytoskeleton of Giardia has been slow to emerge. Perhaps most importantly, although the association of Giardia with diarrhoeal disease has been known for several hundred years, little is known of the mechanism by which Giardia exacts such a toll on its host. What is clear, however, is that the flagella and disk are essential for parasite motility and attachment to host intestinal epithelial cells. Because peristaltic flow expels intestinal contents, attachment is necessary for parasites to remain in the small intestine and cause diarrhoea, underscoring the essential role of the cytoskeleton in virulence. This review presents current day knowledge of the cytoskeleton, focusing on its role in motility and attachment. -
The Potential of Pseudomonas Bacteria As Biocontrol Agents Against Multiple Plant Pathogens
The potential of Pseudomonas bacteria as biocontrol agents against multiple plant pathogens Sophie Elizabeth Clough Doctor of Philosophy University of York Biology September 2020 Abstract Plant pathogenic bacterium Ralstonia solanacearum (the causative agent of bacterial wilt), and plant parasitic nematodes Globodera pallida (white potato cyst nematode) and Meloidogyne incognita (root-knot nematode) have devastating impacts on several economically important crops globally. While these pathogens are traditionally treated with agrochemicals, their use is in decline due to legal restrictions and harmful impacts on the environment. One environmentally- friendly alternative to agrochemicals could be biocontrol, which takes advantage of naturally occurring plant growth-promoting bacteria. While recent studies have shown promising results, there is no clear screening pipeline to identify and validate successful biocontrol strains with broad activity against multiple different pathogen species. This thesis establishes a screening method to identify effective Pseudomonas biocontrol agents to both bacterial and nematode pathogens using a combination of in vitro laboratory assays, comparative genomics, mass spectrometry and greenhouse experiments. It was found that Pseudomonas strains suppressed both pathogens, with strains CHA0, MVP1-4 and Pf-5 showing high activity. Several secondary metabolite clusters were identified and the suppressive role of DAPG, orfamides A and B and pyoluteorin antimicrobials were experimentally verified. Experimental evolution was used to show that R. solanacearum can evolve tolerance to Pseudomonas strains during prolonged exposure in vitro. However, further work is needed to test whether the evolution of tolerance could limit Pseudomonas biocontrol efficiency in the field. High nematode suppression by all Pseudomonas strains was observed in laboratory assays. Moreover, clear behavioural and developmental changes were observed in response to tested individual compounds. -
2-Amino-1,3,4-Thiadiazoles in Leishmaniasis
Review Future Prospects in the Treatment of Parasitic Diseases: 2‐Amino‐1,3,4‐Thiadiazoles in Leishmaniasis Georgeta Serban Pharmaceutical Chemistry Department, Faculty of Medicine and Pharmacy, University of Oradea, 29 Nicolae Jiga, 410028 Oradea, Romania; [email protected]; Tel: +4‐0756‐276‐377 Received: 22 March 2019; Accepted: 17 April 2019; Published: 19 April 2019 Abstract: Neglected tropical diseases affect the lives of a billion people worldwide. Among them, the parasitic infections caused by protozoan parasites of the Trypanosomatidae family have a huge impact on human health. Leishmaniasis, caused by Leishmania spp., is an endemic parasitic disease in over 88 countries and is closely associated with poverty. Although significant advances have been made in the treatment of leishmaniasis over the last decade, currently available chemotherapy is far from satisfactory. The lack of an approved vaccine, effective medication and significant drug resistance worldwide had led to considerable interest in discovering new, inexpensive, efficient and safe antileishmanial agents. 1,3,4‐Thiadiazole rings are found in biologically active natural products and medicinally important synthetic compounds. The thiadiazole ring exhibits several specific properties: it is a bioisostere of pyrimidine or benzene rings with prevalence in biologically active compounds; the sulfur atom increases lipophilicity and combined with the mesoionic character of thiadiazoles imparts good oral absorption and good cell permeability, resulting in good bioavailability. This review presents synthetic 2‐amino‐1,3,4‐thiadiazole derivatives with antileishmanial activity. Many reported derivatives can be considered as lead compounds for the synthesis of future agents as an alternative to the treatment of leishmaniasis. Keywords: 2‐amino‐1,3,4‐thiadiazole; neglected tropical diseases; protozoan parasites; Leishmania spp.; antileishmanial activity; inhibitory concentration 1. -
Molecular Characterization of Leishmania RNA Virus 2 in Leishmania Major from Uzbekistan
G C A T T A C G G C A T genes Article Molecular Characterization of Leishmania RNA virus 2 in Leishmania major from Uzbekistan 1, 2,3, 1,4 2 Yuliya Kleschenko y, Danyil Grybchuk y, Nadezhda S. Matveeva , Diego H. Macedo , Evgeny N. Ponirovsky 1, Alexander N. Lukashev 1 and Vyacheslav Yurchenko 1,2,* 1 Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov University, 119435 Moscow, Russia; [email protected] (Y.K.); [email protected] (N.S.M.); [email protected] (E.N.P.); [email protected] (A.N.L.) 2 Life Sciences Research Centre, Faculty of Science, University of Ostrava, 71000 Ostrava, Czech Republic; [email protected] (D.G.); [email protected] (D.H.M.) 3 CEITEC—Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic 4 Department of Molecular Biology, Faculty of Biology, Moscow State University, 119991 Moscow, Russia * Correspondence: [email protected]; Tel.: +420-597092326 These authors contributed equally to this work. y Received: 19 September 2019; Accepted: 18 October 2019; Published: 21 October 2019 Abstract: Here we report sequence and phylogenetic analysis of two new isolates of Leishmania RNA virus 2 (LRV2) found in Leishmania major isolated from human patients with cutaneous leishmaniasis in south Uzbekistan. These new virus-infected flagellates were isolated in the same region of Uzbekistan and the viral sequences differed by only nineteen SNPs, all except one being silent mutations. Therefore, we concluded that they belong to a single LRV2 species. New viruses are closely related to the LRV2-Lmj-ASKH documented in Turkmenistan in 1995, which is congruent with their shared host (L. -
Manual for the Diagnosis and Treatment of Leishmaniasis
Republic of the Sudan Federal Ministry of Health Communicable and Non-Communicable Diseases Control Directorate MANUAL FOR THE DIAGNOSIS AND TREATMENT OF LEISHMANIASIS November 2017 Acknowledgements The Communicable and Non-Communicable Diseases Control Directorate (CNCDCD), Federal Ministry of Health, Sudan, would like to acknowledge all the efforts spent on studying, controlling and reducing morbidity and mortality of leishmaniasis in Sudan, which culminated in the formulation of this manual in April 2004, updated in October 2014 and again in November 2017. We would like to express our thanks to all National institutions, organizations, research groups and individuals for their support, and the international organization with special thanks to WHO, MSF and UK- DFID (KalaCORE). I Preface Leishmaniasis is a major health problem in Sudan. Visceral, cutaneous and mucosal forms of leishmaniasis are endemic in various parts of the country, with serious outbreaks occurring periodically. Sudanese scientists have published many papers on the epidemiology, clinical manifestations, diagnosis and management of these complex diseases. This has resulted in a better understanding of the pathogenesis of the various forms of leishmaniasis and has led to more accurate and specific diagnostic methods and better therapy. Unfortunately, many practitioners are unaware of these developments and still rely on outdated diagnostic procedures and therapy. This document is intended to help those engaged in the diagnosis, treatment and nutrition of patients with various forms of leishmaniasis. The guidelines are based on publications and experience of Sudanese researchers and are therefore evidence based. The guidelines were agreed upon by top researchers and clinicians in workshops organized by the Leishmaniasis Control response at the Communicable and Non-Communicable Diseases Control Directorate, Federal Ministry of Health, Sudan. -
Viewed in Detail
NEGLECTED TROPICAL DISEASE CHEMOTHERAPY: MECHANISTIC CHARACTERIZATION OF ANTITRYPANOSOMAL DIHYDROQUINOLINES AND DEVELOPMENT OF A HIGH THROUGHPUT ANTILEISHMANIAL SCREENING ASSAY DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy from the Graduate School of The Ohio State University By Shanshan He, M.S. ****** Graduate Program in Pharmaceutical Sciences The Ohio State University 2012 Dissertation Committee: Karl A Werbovetz, Ph.D., Advisor Mark E Drew, Ph.D. Co-advisor Werner Tjarks, Ph.D. Juan D D Alfonzo, Ph.D Copyright by Shanshan He 2012 ABSTRACT Human African trypanosomiasis (HAT) and leishmaniasis are identified by the World Health Organization (WHO) as neglected tropical diseases (NTDs), together with Chagas disease and Buruli ulcer. These NTDs mostly affect people in remote or rural area, and there are very limited control and therapeutic options. The investment on research and development against NTDs is insufficient. Human African trypanosomiasis (HAT) is a vector-borne parasitic disease caused by Trypanosoma brucei subspecies. Transmitted by the tsetse fly, the disease mainly affects rural populations in sub-Saharan Africa and is fatal if untreated. New drugs are needed against HAT that are safe, affordable, easy to administer, active against first and second stage disease, and effective against both subspecies of T. brucei (11, 139). From medicinal chemistry investigation in Karl Werbovetz group, several N1-substituted 1,2-dihydroquinoline-6-ols were discovered displaying nanomolar IC50 values in vitro against T. b. rhodesiense and selectivity indexes (SI) up to >18,000 (39). OSU-40 (1- benzyl-1,2-dihydro-2,2,4–trimethylquinolin-6-yl acetate) is selectively potent against T.