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PublicationArticle Comparative proteomics and glycoproteomics of plasma proteins in Indian visceral leishmaniasis(BioMed Central Ltd., 2014) Arup K. Bag; Sutapa Saha; Shyam Sundar; Bibhuti Saha; Abhijit Chakrabarti; Chitra MandalBackground: Visceral leishmaniasis (VL) is a deadly parasitic diseases caused by Leishmania donovani; it is a major health problem in many countries. A lack of proper understanding of the disease biology, poor diagnostic methods and increasing drug resistance are the main reasons for the growing burden of VL infection. Comparative plasma proteomics are a relatively useful technique that can be used to investigate disease-associated alterations that can help in understanding host responses against pathogens, and might be useful in disease management and diagnosis.Result: In this study, a comparative proteomics and glycoproteomics approach using 2DE and 2D-DIGE was employed between early diagnosed VL patients of all age groups and healthy endemic and non-endemic controls in order to aid the recognition of disease-associated alterations in host plasma. Comparative proteomics was performed by the depletion of seven highly abundant plasma proteins. Comparative glycoproteomics was performed by the depletion of albumin and IgG, followed by purification of plasma glycoproteins using a multi lectin affinity column. From these two approaches, 39 differentially expressed protein spots were identified and sequenced using MALDI-TOF/TOF mass spectrometry. This revealed ten distinct proteins that appeared in multiple spots, suggesting micro-heterogeneity. Among these proteins, alpha-1-antitrypsin, alpha-1-B glycoprotein and amyloid-A1 precursor were up-regulated, whereas vitamin-D binding protein, apolipoprotein-A-I and transthyretin were down-regulated in VL. Alterations in the levels of these proteins in VL-infected plasma were further confirmed by western blot and ELISA.Conclusions: These proteins may be involved in the survival of parasites, resisting neutrophil elastase, and in their multiplication in macrophages, potentially maintaining endogenous anti-inflammatory and immunosuppressive conditions. Consequently, the results of this study may help in understanding the host response against L.donovani, which could help in the discovery of new drugs and disease management. Finally, these alterations on protein levels might be beneficial in improving early diagnosis considering those as biomarkers in Indian VL. © 2014 Bag et al.; licensee BioMed Central Ltd.PublicationArticle Ocular manifestations and human immunodeficiency virus retinopathy in patients with acquired immunodeficiency syndrome in North India(2006) V. Satya Suresh Attili; Vijay P. Singh; A.V. Bhaskar Reddy; Datla V. Varma; Madhukar Rai; Kumar A. Gulati; Shyam SundarAim: To evaluate the spectrum of eye diseases in patients with human immunodeficiency virus, with special reference to human immunodeficiency virus retinopathy and its risk factors. Methods: All patient with human immunodeficiency virus attending the Infectious Disease Clinic at Sir Sunderlal Hospital, Institute of Medical Sciences, Banaras Hindu University, India, between January 2001 and December 2003 were enrolled. All patients underwent a thorough eye examination. Patients with acquired immunodeficiency syndrome retinopathy were analysed separately for predisposing factors. The risk factors analysed were positive C-reactive protein, low CD4 levels, associated central nervous system infections, and other eye diseases. Statistical analysis was done using Medcalc version 7.5. Results: Of 460 analysable patients, 88 patients (19%) had some eye manifestations, and 54 patients had human immunodeficiency virus retinopathy. Univariate analysis disclosed that immunosuppression (CD4 levels, <20/μL), positive C-reactive protein, associated eye lesions, and any central nervous system pathology were significant risk factors for the development of human immunodeficiency virus/acquired immunodeficiency syndrome retinopathy. Conclusions: Human immunodeficiency virus could be a risk factor for retinopathy as a significant number of patients did not have any other findings or risk factors for the development of retinopathy. However, it would be premature to draw definitive conclusions about the risk factors, as the number of patients analysed was small. © 2006 Scientific Communications International Limited.PublicationArticle 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 BoelaertBackground: 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.PublicationArticle Exploiting knowledge on pharmacodynamics-pharmacokinetics for accelerated anti-leishmanial drug discovery/development(Taylor and Francis Ltd, 2019) Shyam Sundar; Neha Agrawal; Bhawana SinghIntroduction: Being on the top list of neglected tropical diseases, leishmaniasis has been marked for elimination by 2020. In the light of small armamentarium of drugs and their associated drawbacks, the understanding of pharmacodynamics and/or pharmacokinetics becomes a priority to achieve and sustain disease elimination. Areas covered: The authors have looked into pharmacological aspects of existing and emerging drugs for treatment of leishmaniasis. An in-depth understanding of pharmacodynamics and pharmacokinetics (PKPD) provides a rationale for drug designing and optimizing the treatment strategies. It forms a key to prevent drug resistance and avoid drug-associated adverse effects. The authors have compiled the researches on the PKPD of different anti-leishmanial formulations that have the potential for improved and/or effective disease intervention. Expert opinion: Understanding the pharmacological aspects of drugs forms the basis for the clinical application of novel drugs. Tailoring drug dosage and individualized treatment can avoid the adverse events and bridge gap between the in vitro models and their clinical application. An integrated approach, with pragmatic use of technological advances can improve phenotypic screening and physiochemical properties of novel drugs. Concomitantly, this can serve to improve clinical efficacies, reduce the incidence of relapse and accelerate the drug discovery/development process for leishmaniasis elimination. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.PublicationReview Leishmaniasis: Vaccine candidates and perspectives(2012) Bhawana Singh; Shyam SundarLeishmania is a protozoan parasite and a causative agent of the various clinical forms of leishmaniasis. High cost, resistance and toxic side effects of traditional drugs entail identification and development of therapeutic alternatives. The sound understanding of parasite biology is key for identifying novel drug targets, that can induce the cell mediated immunity (mainly CD4+ and CD8+ IFN- gamma mediated responses) polarized towards a Th1 response. These aspects are important in designing a new vaccine along with the consideration of the candidates with respect to their ability to raise memory response in order to improve the vaccine performance. This review is an effort to identify molecules according to their homology with the host and their ability to be used as potent vaccine candidates. © 2012.PublicationArticle Prevalence of sand flies and Leishmania donovani infection in a natural population of female Phlebotomus argentipes in Bihar state, India(2012) Puja Tiwary; Dinesh Kumar; Rudra Pratap Singh; Madhukar Rai; Shyam SundarLeishmaniasis is a vector-borne disease, and in the Indian subcontinent the female Phlebotomus argentipes is the vector for Leishmania donovani. However, data on the extent of sand fly infection rates in natural settings using molecular methods have not been extensively reported in India. In this study a PCR technique was applied targeting the 18S rRNA encoding region to determine the prevalence of Leishmania infection in female P. argentipes captured in the field. For this study, sand flies were collected from 897 houses selected from 50 villages endemic for visceral leishmaniasis (VL) in Muzaffarpur district, Bihar state, using CDC miniature light traps and mouth aspirators. A total of 14,585 sand flies were collected of which 449 were female P. argentipes divided into 132 pools. Molecular detection using PCR targeting the 18S rRNA gene was carried out for the identification of P. argentipes and Leishmania. The overall prevalence of infection was 4.90-17.37% for L. donovani in female P. argentipes in endemic regions of Bihar state. In this study no correlation was found between the presence of infected sand flies and the occurrence of clinical VL. This study provides the first report evaluating the prevalence of Leishmania infection in sand flies in a region endemic for VL in India. Sergentomyia species are the most common species of sand fly. Knowledge of the infection rate in female P. argentipes may help in predicting severity of disease and in vector elimination programs. © Copyright 2012, Mary Ann Liebert, Inc.PublicationArticle Molecular docking, structure-activity relationship and biological evaluation of the anticancer drug monastrol as a pteridine reductase inhibitor in a clinical isolate of Leishmania donovani(2010) Jaspreet Kaur; Shyam Sundar; Neeloo SinghObjectives: Using the pteridine reductase (PTR1) enzyme of Leishmania as the target, the objective of our study was to find a drug candidate that can enter the clinical development process after being evaluated for safety and efficacy in animals. Methods: Monastrol (R) and (S) enantiomers were docked using the QUANTUM program into the active site of a Leishmania donovani PTR1 (LdPTR1) homology model. A structure-activity relationship based on a homology model of a recombinant enzyme was substantiated by a recombinant enzyme inhibition assay. We adapted an L. donovani (transfected with green fluorescent protein) intramacrophage amastigote screening assay as a cellular model for leishmaniasis. Furthermore, since the clinicopathological features and immunopathological mechanisms of visceral leishmaniasis (VL) in a hamster model are remarkably similar to those of human disease, systemic infection of hamsters with L. donovani was utilized to collect in vivo data for monastrol. Results: Both monastrol (R) and (S) enantiomers fit well in the ligand-binding pocket of LdPTR1. Monastrol exhibits a Ki value of 0.428 μM in the recombinant enzyme inhibition assay. We confirm monastrol as a potent inhibitor of PTR1 in Leishmania; it inhibits proliferation of amastigotes with an IC50 (50% inhibitory concentration) of 10 μM in macrophage cultures infected with an L. donovani clinical isolate, with no host cytotoxicity. We also show that in experimental animals, oral administration of a 5 mg/kg dose of monastrol on two alternate days inhibits 50% of parasite growth, giving therapeutic backing to the use of monastrol as a potent antileishmanial in human VL cases. Conclusions: To our knowledge, this is the first report presenting monastrol as a potent oral antileishmanial. © The Author 2010.PublicationArticle Identification of new antigens in visceral leishmaniasis by expression cloning and immunoblotting with sera of Kala-Azar patients from Bihar, India(2005) Stephan M. Theinert; Rajatava Basu; Michael Forgber; Syamal Roy; Shyam Sundar; Peter WaldenSera of kala-azar patients from Bihar, India, were used to identify Leishmania donovani antigens encoded by a phage expression library. Ten antigens were identified, five of which have not been described as leishmania antigens before. The antigens specifically react with sera of leishmania-infected patients but not of toxoplasma-or plasmodium-infected patients. Copyright © 2005, American Society for Microbiology. All Rights Reserved.PublicationArticle Evaluation of Cardiovascular Risk Profile and Risk Scores of Antiretroviral Therapy‑naïve HIV Patients in Eastern India(Wolters Kluwer Medknow Publications, 2024) Manaswi Chaubey; Jaya Chakravarty; Rishabh Gupta; Parth Jethwani; Rahul Puri; Shyam SundarIntroduction: People living with human immunodeficiency virus (PLHIV) are known to have an increased prevalence of traditional cardiovascular risk factors and are at a higher risk of cardiovascular disease (CVD). This study was done to assess the CVD risk factors in treatment naïve PLHIV in a center of the national program. Methods: In this cross-sectional explorative study, traditional CVD risk factors were assessed, and 10-year Framingham and atherosclerotic cardiovascular disease (ASCVD) risk score were calculated in treatment naïve PLHIV attending the antiretroviral therapy (ART) center, IMS, BHU. Results: The study included 337 ART naïve patients. The prevalence of CVD risk factors in treatment naïve PLHIV - were low high-density lipoprotein cholesterol levels (81.4%), high triglyceride levels (32.7%), smoking (32.3%), obesity (13.6%), hypertension (5%), diabetes (2.7%), and high low-density lipoprotein cholesterol levels (2.1%). Moderate-to-high 10-year Framingham Risk Score and American Heart Association/American College of Cardiology 10-year ASCVD risk score were 10.8% and 8.9%, respectively. In Framingham Risk Score, age ≥40 years (odds ratio [OR] - 131) (95% confidence interval [CI] - 6.5–1043) alcohol intake (OR - 5.14 [95% CI - 1.82–14.46] and presence of tuberculosis (OR - 4.78) (95% CI - 1.48-15.40), while in ASCVD risk score history of alcohol intake (OR - 26.20 [95% CI - 3.1-216.8] were at higher risk of CVD in multivariate variate analysis. Conclusion: CVD risk factors were common among ART naïve patient. Thus, screening, education, and treatment of CVD risk factors should be done in these patients at initiation of care. © 2024 Journal of Global Infectious Diseases.PublicationReview Visceral leishmaniasis: What are the needs for diagnosis, treatment and control?(2007) François Chappuis; Shyam Sundar; Asrat Hailu; Hashim Ghalib; Suman Rijal; Rosanna W. Peeling; Jorge Alvar; Marleen BoelaertVisceral leishmaniasis (VL) is a systemic protozoan disease that is transmitted by phlebotomine sandflies. Poor and neglected populations in East Africa and the Indian sub-continent are particularly affected. Early and accurate diagnosis and treatment remain key components of VL control. In addition to improved diagnostic tests, accurate and simple tests are needed to identify treatment failures. Miltefosine, paromomycin and liposomal amphotericin B are gradually replacing pentavalent antimonials and conventional amphotericin B as the preferred treatments in some regions, but in other areas these drugs are still being evaluated in both mono- and combination therapies. New diagnostic tools and new treatment strategies will only have an impact if they are made widely available to patients.