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Assessing L. donovani Skin Parasite Load: A Proof of Concept Study of a Microbiopsy Device in an Indian Setting
(Frontiers Media S.A., 2021) Kristien Cloots; Om Prakash Singh; Abhishek Kumar Singh; Gert Van der Auwera; Prashant Kumar; Mallikarjuna Rao Gedda; Tulika Kumari Rai; Epco Hasker; Shyam Sundar; Marleen Boelaert
Background: In the endgame of the elimination initiative of visceral leishmaniasis (VL) on the Indian subcontinent, one of the main questions remaining is whether asymptomatically infected individuals also contribute to transmission. We piloted a minimally invasive microbiopsy device that could help answer this question. While the potential of this device has been previously illustrated in Ethiopia, no such information is available for the setting of the Indian subcontinent. In this proof of concept study we aimed to assess 1) to what extent skin parasite load obtained with the new microbiopsy device correlates with disease status, 2) to what extent skin parasite load correlates with blood parasite load in the same subject, and 3) to what extent the skin parasite load obtained from different sampling sites on the body correlates with one another. Methods: We performed a pilot study in Bihar, India, including 29 VL patients, 28 PKDL patients, 94 asymptomatically infected individuals, 22 endemic controls (EC), and 28 non-endemic controls (NEC). Presence of infection with L. donovani in the blood was assessed using Direct Agglutination Test, rK39 ELISA, Whole Blood Analysis measuring IFN-γ and qPCR. A skin sample was collected with the microbiopsy device on two different locations on the body. PKDL patients provided a third skin sample from the edge of a PKDL lesion. Parasite load in the skin was measured by qPCR. Findings: We found a clear correlation between the skin parasite load obtained with the microbiopsy device and disease status, with both higher skin parasite loads and higher proportions of positive skin samples in VL and PKDL patients compared to asymptomatics, EC, and NEC. No clear correlation between skin parasite load and blood parasite load was found, but a moderate correlation was present between the skin parasite load in arm and neck samples. In addition, we found four positive skin samples among asymptomatic individuals, and 85% of PKDL lesions tested positive using this microbiopsy device. Conclusions: In line with previous pilot studies, our results from an Indian setting suggest that the microbiopsy device provides a promising tool to measure skin parasite load, and – if validated by xenodiagnosis studies – could facilitate much needed larger scale studies on infectiousness of human subgroups. In addition, we advocate further evaluation of this device as a diagnostic tool for PKDL. © Copyright © 2021 Cloots, Singh, Singh, Van der Auwera, Kumar, Gedda, Rai, Hasker, Sundar and Boelaert.
Antimony toxicity
(MDPI, 2010) Shyam Sundar; Jaya Chakravarty
Antimony toxicity occurs either due to occupational exposure or during therapy. Occupational exposure may cause respiratory irritation, pneumoconiosis, antimony spots on the skin and gastrointestinal symptoms. In addition antimony trioxide is possibly carcinogenic to humans. Improvements in working conditions have remarkably decreased the incidence of antimony toxicity in the workplace. As a therapeutic, antimony has been mostly used for the treatment of leishmaniasis and schistosomiasis. The major toxic side-effects of antimonials as a result of therapy are cardiotoxicity (~9% of patients) and pancreatitis, which is seen commonly in HIV and visceral leishmaniasis co-infections. Quality control of each batch of drugs produced and regular monitoring for toxicity is required when antimonials are used therapeutically. © 2010 by the authors; licensee MDPI, Basel, Switzerland.
Developing imidazole analogues as potential inhibitor for Leishmania donovani trypanothione reductase: Virtual screening, molecular docking, dynamics and ADMET approach
(Taylor and Francis Ltd., 2015) Rajan Kumar Pandey; Drista Sharma; Tarun Kumar Bhatt; Shyam Sundar; Vijay Kumar Prajapati
Visceral leishmaniasis (VL) affects Indian subcontinent, African and South American continent, and it covers 70 countries worldwide. Visceral form of leishmaniasis is caused by Leishmania donovani in Indian subcontinent which is lethal if left untreated. Extensive resistance to antileishmanial drugs such as sodium stibogluconate, pentamidine and miltefosine and their decreased efficacy has been reported in the endemic region. Amphotericin B drug has shown good antileishmanial activity with significant toxicity, but its cost of treatment has limited the outreach of this treatment to affected people living in endemic zone. So, there is an urgent need to identify new antileishmanial drugs with excellent activity and minimal toxicity issues. Trypanothione reductase, a component of antioxidant system, is necessary for parasite growth and survival to raise infection. To develop potential inhibitor, we docked nine hundred and eighty-four 5-nitroimidazole analogues along with clomipramine which is a well-known inhibitor for TR. Total one hundred and forty-seven 5-nitroimidazole analogues with better docking score than clomipramine were chosen for ADMET and QikProp studies. Among these imidazole analogues, total twenty-four imidazole analogues and clomipramine were chosen on the basis of their ADMET, QikProp, and prime MM-GBSA study. Later on, two analogues with best MM-GBSA dG bind were undergone molecular dynamic simulation to ensure protein-ligand interactions. Using above approach, we confirm that ethyl 2-acetyl-5-[4-butyl-2-(3-hydroxypentyl)-5-nitro-1H-imidazol-1-yl]pent-2-enoate can be a drug candidate against L. donovani for the treatment of VL in the Indian subcontinent. © 2015 Taylor & Francis.
A subset of neutrophils expressing markers of antigen-presenting cells in human visceral leishmaniasis
(Oxford University Press, 2016) Smriti Sharma; Richard E. Davis; Shweta Srivastva; Susanne Nylén; Shyam Sundar; Mary E. Wilson
Background. Visceral leishmaniasis (VL) is a potentially fatal parasitic disease associated with fever, cachexia and impaired protective T-cell responses against the parasite. Methods. Peripheral blood leukocytes from 105 subjects with VL and healthy control subjects from the endemic region of Muzaffarpur, Bihar, India, were compared using flow cytometry and reverse-transcriptase quantitative polymerase chain reaction. Findings were correlated with clinical data. Results. An expanded population of low-density neutrophils that expressed HLA-DR, CD80 and CD86 was observed in subjects with VL. This neutrophil population contracted after successful treatment of disease. Plasma from patients with acute VL was able to induce similar high-level HLA-DR expression in neutrophils from healthy subjects. HLA-DR+ neutrophils from subjects with VL did not stimulate T-cell proliferation, but they did express higher programmed cell death ligand-1 (PDL1) than other neutrophils, and lymphocytes of the same subjects expressed high programmed cell death 1 (PD1). Conclusions. Patients with acute VL have expanded circulating low-density neutrophils expressing markers of antigen presentation, which diminish after treatment. Development of HLA-DR+ neutrophils is stimulated, at least in part, by components of plasma from patients with acute disease. Although we found no evidence that they act as antigen-presenting cells, these neutrophils expressed markers implicating a role in T-cell exhaustion. © 2016 Published by Oxford University Press for the Infectious Diseases Society of America.
Leishmaniasis: An update of current pharmacotherapy
(2013) Shyam Sundar; Jaya Chakravarty
Introduction: Leishmaniasis broadly manifests as visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). The treatment of VL is challenging. The duration of treatment is long, and drugs are toxic thereby needing monitoring and hospitalization. Areas covered: Novel therapies such as single dose of liposomal amphotericin B (L-AmB) and multidrug therapy are important breakthrough for VL in the Indian subcontinent and have been recommended as the treatment of choice in this region. African Leishmania donovani is less susceptible to L-AmB, miltefosine and paromomycin as compared to the Indian strains, and the treatment of choice remains a 17-day combination therapy of pentavalent antimonials (SBv) and paromomycin. L-AmB at a total dose of 18-21 mg/kg is the recommended regimen in the Mediterranean region and South America. It is also the treatment of choice for HIV-VL coinfection. Treatment of CL should be decided by the clinical lesions, etiological species and its potential to develop into mucosal leishmaniasis. A literature search on treatment of leishmaniasis was done on PubMed and through Google. Expert opinion: There is an urgent need for exploratory studies with short course, highly efficient regimens such as single dose L-AmB or combination therapy for all the endemic regions of VL. Shorter and more acceptable regimens are needed for the treatment of post-kala-azar dermal leishmaniasis. Treatment of CL remains one of the neglected areas of leishmaniasis as data are scarce and drawn from uncontrolled studies. © 2013 Informa UK, Ltd.
Flow cytometric determination of intracellular non-protein thiols in Leishmania promastigotes using 5-chloromethyl fluorescein diacetate
(2009) Avijit Sarkar; Goutam Mandal; Neeloo Singh; Shyam Sundar; Mitali Chatterjee
Leishmania parasites lack catalase and therefore, their anti-oxidant system hinges primarily upon non-protein thiols; accordingly, depletion of thiols could potentially serve as an effective drug target. We have developed a flow cytometry based assay using 5-chloromethyl fluorescein diacetate based upon its selective staining of non-protein thiols. Its specificity was confirmed using buthionine sulphoximine (a γ-glutamyl cysteine synthetase inhibitor), diamide (an oxidizing agent of intracellular thiols) and N-ethylmaleimide (a covalent modifier of cysteine residues) as evidenced by reduction in fluorescence; furthermore, restoration of fluorescence by N-acetyl cysteine corroborated specificity of 5-chloromethyl fluorescein diacetate to measure non-protein thiols. Differences in basal level of thiols in antimony sensitive and antimony resistant Leishmania field isolates were detected. The depletion of non-protein thiols by conventional anti-leishmanial drugs e.g. antimony and miltefosine was demonstrated. Furthermore, fluorescence was unaffected by depletion of ATP in majority of the strains studied, indicating that 5-chloromethyl fluorescein diacetate is not a substrate for the pump operative in most Leishmania donovani strains. Taken together, measurement of 5-chloromethyl fluorescein diacetate fluorescence is an effective method for monitoring non-protein thiols in Leishmania promastigotes. © 2009 Elsevier Inc. All rights reserved.
Leishmaniasis: treatment, drug resistance and emerging therapies
(Taylor and Francis Ltd, 2019) Shyam Sundar; Jaya Chakravarty; Lalit P Meena
Introduction: Leishmaniasis is one of the most neglected tropical infectious diseases in the world. Emergence of drug resistance and toxicity and high cost of the available drugs with lack of new antileishmanial drugs highlight the need to search for newer molecules with antileishmanial activities. Areas covered: This article describes the currently available antileishmanial drugs and their risk of developing resistance and discusses newer therapies. These include oral lipid-based formulations of amphotericin B, use of different drug delivery systems, and quinolone derivatives–naphthoquinone, buparvaquone, etc. Expert opinion: There are only a handful of antileishmanial drugs, and even fewer in the pipeline. Guideline-based treatment, with proper selection of antileishmanial compound, should be practiced. Combination therapy should be used preferably to prevent or delay drug resistance. As most patients with PKDL (post-kala-azar dermal leishmaniasis) are asymptomatic, it is important that shorter regimens are developed, which will encourage patients to opt for complete treatment. Pharmaceutical industry and “not for profit’ organizations should be encouraged to enhance the efforts in finding clinically effective antileishmanial drugs. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
Resurgence of kala-azar in India: Reasons and remedies
(2000) Shyam Sundar
Current epidemics of kala-azar in India began in early seventies, and has continued since then with surges every few years causing extensive morbidity and mortality. Most of the disease occurs in the state of Bihar, but now newer areas are involved. Epidemics have occurred in Eastern Uttar Pradesh, North Bengal and sporadic cases being reported from different parts of the country, where kala-azar was never seen earlier. Its diagnosis rests upon demonstration of parasites in the tissue aspirates which is often difficult in field conditions, and thus it is often delayed. Growing antimony resistance over last two decades has made treatment extremely difficult, both antimony and pentamidine, in addition to having serious toxicity, have lost their efficacy to a great extent and are no longer the preferred treatment in the hyperendemic areas, and only available drug for these patients remains amphotericin B. Control measures have been grossly inadequate resulting in continued transmission of the disease. In recent years some exciting development have occurred in diagnosis as well as treatment most notably a strip test which can be used even by paramedics in most peripheral areas, similarly lipid formulations of amphotericin B have opened a new vista in the chapter of antileishmanial treatment. Miltefosine in all likelihood will be the first oral antileishmanial drug to be approved for the treatment of kala-azar. Still much work need to be done, little progress has been made in the vaccine effort. Public health measures remain dismal. In the next millennium, as newer diagnostic methods and better treatment become available, combined with aggressive preventive measures like vector control, successful vaccine development and health education for masses, elimination of this dreaded disease can be achieved.
Case study for a vaccine against leishmaniasis
(2013) Jorge Alvar; Simon L. Croft; Paul Kaye; Ali Khamesipour; Shyam Sundar; Steven G. Reed
Leishmaniasis in many ways offers a unique vaccine case study. Two reasons for this are that leishmaniasis is a disease complex caused by several different species of parasite that are highly related, thus raising the possibility of developing a single vaccine to protect against multiple diseases. Another reason is the demonstration that a leishmaniasis vaccine may be used therapeutically as well as prophylactically. Although there is no registered human leishmaniasis vaccine today, immunization approaches using live or killed organisms, as well as defined vaccine candidates, have demonstrated at least some degree of efficacy in humans to prevent and to treat some forms of leishmaniasis, and there is a vigorous pipeline of candidates in development. Current approaches include using individual or combined antigens of the parasite or of salivary gland extract of the parasites' insect vector, administered with or without formulation in adjuvant. Animal data obtained with several vaccine candidates are promising and some have been or will be entered into clinical testing in the near future. There is sufficient scientific and epidemiological justification to continue to invest in the development of vaccines against leishmaniasis. © 2012 Elsevier Ltd.
A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1+MPL-SE vaccine for use in the prevention of visceral leishmaniasis
(2011) Jaya Chakravarty; Subodh Kumar; Sonali Trivedi; Vijay K. Rai; Anup Singh; Jill A. Ashman; Elsa M. Laughlin; Rhea N. Coler; Stuart J. Kahn; Anna Marie Beckmann; Karen D. Cowgill; Steven G. Reed; Shyam Sundar; Franco M. Piazza
Healthy Indian adult volunteers, with or without a history of leishmaniasis, were evaluated for evidence of previous infection with Leishmania donovani based on the direct agglutination test (DAT). Three cohorts of 6 DAT-negative and 6 DAT-positive subjects were enrolled in an open-label, dose-escalating, uncontrolled clinical trial and received three injections of the LEISH-F1+MPL-SE vaccine (consisting of 5μg, 10μg, or 20μg recombinant Leishmania polyprotein LEISH-F1 antigen+25μg MPL®-SE adjuvant). The study injections were given subcutaneously on days 0, 28, and 56, and the subjects were followed through day 168 for safety and immunological endpoints. The vaccine was safe and well-tolerated in DAT-negative and DAT-positive subjects and induced T-cell production of IFN-γ and other cytokines in response to stimulation with the LEISH-F1 antigen. This clinical trial shows that the LEISH-F1+MPL-SE vaccine is safe and immunogenic in healthy subjects with and without history of previous infection with Leishmania donovani. © 2011 Elsevier Ltd.

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