Scholarly Publications
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This community showcases the academic contributions of faculty and researchers at Banaras Hindu University (BHU) and provides a year-wise compilation of publications across disciplines. Institutional Repository BHU
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PublicationArticle Apolipoprotein E Is Upregulated in Blood and Circulating Monocytes of Indian Patients With Visceral Leishmaniasis(John Wiley and Sons Inc, 2024) Gulafsha Kausar; Shashi B. Chauhan; Ritirupa Roy; Shashi Kumar; Christian Engwerda; Susanne Nylen; Rajiv Kumar; Mary E. Wilson; Shyam SundarApolipoprotein E (ApoE) has been associated with several diseases including Parkinson's disease, Alzheimer's and multiple sclerosis. ApoE also has documented immunomodulatory functions. We investigated gene expression in circulating monocytes and in bone marrows of patients with visceral leishmaniasis (VL) living in an endemic area in Bihar, India, and contrasted these with control healthy subjects or other diagnostic bone marrows from individuals in the same region. Samples from VL patients were obtained prior to initiating treatment. Our study revealed significant upregulated expression of the apoE transcript in patients with VL. Furthermore, the levels of ApoE protein were elevated in serum samples of subjects with VL compared with healthy endemic controls. These observations may provide clues regarding the complex interactions between lipid metabolism and immunoregulation of infectious and inflammatory diseases. © 2024 John Wiley & Sons Ltd.PublicationArticle Visceral Leishmaniasis–Human Immunodeficiency Virus–Coinfected Patients Are Highly Infectious to Sandflies in an Endemic Area in India(Oxford University Press, 2024) Om Prakash Singh; Rahul Chaubey; Anurag Kumar Kushwaha; Michael P. Fay; David Sacks; Shyam SundarIn an area endemic with Indian visceral leishmaniasis (VL), we performed direct xenodiagnosis to evaluate the transmission of Leishmania donovani from patients with VL–human immunodeficiency virus (HIV) coinfection to the vector sandflies, Phlebotomus argentipes. Fourteen patients with confirmed VL-HIV coinfection, with a median parasitemia of 42 205 parasite genome/mL of blood, were exposed to 732 laboratory-reared pathogen-free female P argentipes sandflies on their lower arms and legs. Microscopy revealed that 16.66% (122/732) of blood-fed flies were xenodiagnosis positive. Notably, 93% (13/14) of the VL-HIV group infected the flies, as confirmed by quantitative polymerase chain reaction and/or microscopy, and were 3 times more infectious than those who had VL without HIV. © The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved.PublicationReview Chemokines Signature and T Cell Dynamics in Leishmaniasis: Molecular Insight and Therapeutic Application(Cambridge University Press, 2024) Shreya Upadhyay; Shashi Kumar; Vishal Kumar Singh; Rahul Tiwari; Awnish Kumar; Shyam Sundar; Rajiv KumarLeishmaniasis, caused by obligate intracellular Leishmania parasites, poses a significant global health burden. The control of Leishmania infection relies on an effective T cell-dependent immune response; however, various factors impede the host's ability to mount a successful defence. Alterations in the chemokine profile, responsible for cell trafficking to the infection site, can disrupt optimal immune responses and influence the outcome of pathogenesis by facilitating parasite persistence. This review aims to emphasize the significance of the chemokine system in T cell responses and to summarize the current knowledge on the dysregulation of chemokines and their receptors associated with different subsets of T lymphocytes during Leishmaniasis. A comprehensive understanding of the dynamic nature of the chemokine system during Leishmaniasis is crucial for the development of successful immunotherapeutic approaches. © The Author(s), 2024. Published by Cambridge University Press.PublicationReview Post kala-azar dermal leishmaniasis in the Indian sub-continent: challenges and strategies for elimination(Frontiers Media SA, 2023) Awnish Kumar; Vishal Kumar Singh; Rahul Tiwari; Prasoon Madhukar; Rajneesh; Shashi Kumar; Vibhav Gautam; Christian Engwerda; Shyam Sundar; Rajiv KumarVisceral leishmaniasis (VL) is a severe and often fatal form of leishmaniasis caused by Leishmania donovani in the Indian sub-continent. Post Kala-azar Dermal Leishmaniasis (PKDL) is a late cutaneous manifestation of VL, typically occurring after apparent cure of VL, but sometimes even without a prior history of VL in India. PKDL serves as a significant yet neglected reservoir of infection and plays a crucial role in the transmission of the disease, posing a serious threat to the VL elimination program in the Indian sub-continent. Therefore, the eradication of PKDL should be a priority within the current VL elimination program aimed at achieving a goal of less than 1 case per 10,000 in the population at the district or sub-district levels of VL endemic areas. To accomplish this, a comprehensive understanding of the pathogenesis of PKDL is essential, as well as developing strategies for disease management. This review provides an overview of the current status of diagnosis and treatment options for PKDL, highlighting our current knowledge of the immune responses underlying disease development and progression. Additionally, the review discusses the impact of PKDL on elimination programs and propose strategies to overcome this challenge and achieve the goal of elimination. By addressing the diagnostic and therapeutic gaps, optimizing surveillance and control measures, and implementing effective intervention strategies, it is possible to mitigate the burden of PKDL and facilitate the successful elimination of VL in the Indian sub-continent. Copyright © 2023 Kumar, Singh, Tiwari, Madhukar, Rajneesh, Kumar, Gautam, Engwerda, Sundar and Kumar.PublicationArticle Safety and Effectiveness of Miltefosine in Post-Kala-Azar Dermal Leishmaniasis: An Observational Study(Oxford University Press, 2023) Shyam Sundar; Jitendra Singh; Anju Dinkar; Neha AgrawalBackground: Post-kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis. Oral miltefosine (MF) is the first-line treatment for PKDL patients in South Asia. This study assessed the safety and effectiveness of MF therapy after 12 months of follow-up to explore more precise data. Methods: In this observational study, 300 confirmed PKDL patients were enrolled. MF with the usual dose was administered to all patients for 12 weeks and followed up for 1 year. Clinical evolution was recorded systematically by photographs at screening and at 12 weeks, 6 months, and 12 months after treatment onset. Definitive cure consisted of disappearance of skin lesions with a negative PCR at 12 weeks or with >70% of lesions, disappearing or fading at 12-month follow-up. Patients with reappearing clinical features and any positive diagnostics of PKDL during the follow-up were considered as nonresponsive. Results: Among 300 patients, 286 (95.3%) completed 12 weeks of treatment. The per-protocol cure rate at 12 months was 97%, but 7 patients relapsed and 51 (17%) were lost to 12-month follow-up, resulting in a final cure rate of only 76%. Eye-related adverse events were noted in 11 (3.7%) patients and resolved in most (72.7%) within 12 months. Unfortunately, 3 patients had persistent partial vision loss. Mild to moderate gastrointestinal side effects were seen in 28% patients. Conclusions: Moderate effectiveness of MF was observed in the present study. A significant number of patients developed ocular complications, and thus MF for treatment for PKDL should be suspended and replaced with a safer alternative regimen. © 2023 The Author(s). Published by Oxford University Press on behalf of Infectious Diseases Society of America.PublicationArticle Coalition of Biological Agent (Melatonin) with Chemotherapeutic Agent (Amphotericin B) for Combating Visceral Leishmaniasis via Oral Administration of Modified Solid Lipid Nanoparticles(American Chemical Society, 2023) Shabi Parvez; Ganesh Yadagiri; Kanika Arora; Aaqib Javaid; Anurag Kumar Kushwaha; Om Prakash Singh; Shyam Sundar; Shyam Lal MudavathIn this study, 2-hydroxypropyl-β-cyclodextrin (HPβCD) grafted solid lipid nanoparticle (SLN)-based bioconjugate was synthesized and used for administering a combination of melatonin (Mel) and amphotericin B (AmB) orally for effective visceral leishmaniasis (VL) treatment. The formulations (HPCD-Mel-AmB SLN) were synthesized by the emulsion solvent evaporation method. HPCD-Mel-AmB SLN showed a high loading capacity and a high entrapment efficiency of AmB (% DL = 9.0 ± 0.55 and % EE = 87.9 ± 0.57) and Mel (% DL = 7.5 ± 0.51 and % EE = 63 ± 6.24). The cumulative percent release of AmB and Mel was 66.10 and 73.06%, respectively, up to 72 h. Time-dependent cellular uptake was noticed for HPCD-Mel-AmB SLN for 4 h. Further, HPCD-Mel-AmB SLN did not show any toxic effects on J774A.1 macrophages and Swiss albino mice. HPCD-Mel-AmB SLN (10 mg/kg ×5 days, p.o.) has significantly diminished (98.89%) the intracellular parasite load in liver tissues of L. donovani-infected BALB/c mice, subsequently highlighting the role of melatonin toward an effective strategy in combating leishmanial infection. Therefore, these results indicated that administration of HPCD-Mel-AmB SLN improve the therapeutic index of the first-line drug in addition to the introduction of biological agent and would be a promising therapeutic candidate for effective VL therapy. In the present study, the objective is to test the efficacy of the chemotherapeutic approach in combination with a biological immunomodulatory agent against leishmanial infection using in vitro and in vivo studies. This information suggests that melatonin could be an efficacious and potent antileishmanial agent. © 2023 American Chemical Society. All rights reserved.PublicationArticle Increased amphiregulin expression by CD4+ T cells from individuals with asymptomatic Leishmania donovani infection(John Wiley and Sons Inc, 2022) Siddharth Sankar Singh; Shashi Bhushan Chauhan; Susanna SS Ng; Dillon Corvino; Fabian de Labastida Rivera; Jessica A Engel; Nic Waddell; Pamela Mukhopadhay; Rebecca L Johnston; Lambros T Koufariotis; Susanne Nylen; Om Prakash Singh; Christian R Engwerda; Rajiv Kumar; Shyam SundarObjectives: There is an urgent need to be able to identify individuals with asymptomatic Leishmania donovani infection, so their risk of progressing to VL and transmitting parasites can be managed. This study examined transcriptional markers expressed by CD4+ T cells that could distinguish asymptomatic individuals from endemic controls and visceral leishmaniasis (VL) patients. Methods: CD4+ T cells were isolated from individuals with asymptomatic L. donovani infection, endemic controls and VL patients. RNA was extracted and RNAseq employed to identify differentially expressed genes. The expression of one gene and its protein product during asymptomatic infection were evaluated. Results: Amphiregulin (AREG) was identified as a distinguishing gene product in CD4+ T cells from individuals with asymptomatic L. donovani infection, compared to VL patients and healthy endemic control individuals. AREG levels in plasma and antigen-stimulated whole-blood assay cell culture supernatants were significantly elevated in asymptomatic individuals, compared to endemic controls and VL patients. Regulatory T (Treg) cells were identified as an important source of AREG amongst CD4+ T-cell subsets in asymptomatic individuals. Conclusion: Increased Treg cell AREG expression was identified in individuals with asymptomatic L. donovani infection, suggesting the presence of an ongoing inflammatory response in these individuals required for controlling infection and that AREG may play an important role in preventing inflammation-induced tissue damage and subsequent disease in asymptomatic individuals. © 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.PublicationReview Domestic mammals as reservoirs for Leishmania donovani on the Indian subcontinent: Possibility and consequences on elimination(John Wiley and Sons Inc, 2022) Anurag Kumar Kushwaha; Breanna M. Scorza; Om Prakash Singh; Edgar Rowton; Phillip Lawyer; Shyam Sundar; Christine A. PetersenLeishmania donovani is the causative agent of historically anthroponotic visceral leishmaniasis (VL) on the Indian subcontinent (ISC). L. donovani is transmitted by the sand fly species Phlebotomus argentipes. Our collaborative group and others have shown that sand flies trapped outside in endemic villages have fed on cattle and dogs in addition to people. Domestic animals are reservoirs for L. donovani complex spp., particularly L. infantum, in other endemic areas. Multiple studies using quantitative PCR or serological detection methods have demonstrated that goats, cattle, rats and dogs were diagnostically positive for L. donovani infection or exposure in eastern Africa, Bangladesh, Nepal and India. There is a limited understanding of the extent to which L. donovani infection of domestic animals drives transmission to other animals or humans on the ISC. Evidence from other vector-borne disease elimination strategies indicated that emerging infections in domestic species hindered eradication. The predominant lesson learned from these other situations is that non-human reservoirs must be identified, controlled and/or prevented. Massive efforts are underway for VL elimination on the Indian subcontinent. Despite these herculean efforts, residual VL incidence persists. The spectre of an animal reservoir complicating elimination efforts haunts the final push towards full VL control. Better understanding of L. donovani transmission on the Indian subcontinent and rigorous consideration of how non-human reservoirs alter VL ecology are critical to sustain elimination goals. © 2021 Wiley-VCH GmbH.PublicationArticle IL-10 and TGF-β Induced Arginase Expression Contributes to Deficient Nitric Oxide Response in Human Visceral Leishmaniasis(Frontiers Media S.A., 2021) Manu Kupani; Smriti Sharma; Rajeev Kumar Pandey; Rajiv Kumar; Shyam Sundar; Sanjana MehrotraNitric oxide (NO) is an anti-microbial effector of the innate immune system which plays major role in non-specific killing of various pathogens including protozoan parasites. However, due to subversion of the host’s immune processes by pathogens, suboptimal production of NO is frequently found in many infection models. Previous studies have shown suppressed NO production during Leishmania donovani infection, the causative agent of visceral leishmaniasis (VL). Availability of L-Arginine, a semi-essential amino acid is required for inducible nitric oxide synthase (iNOS) mediated NO production. However, arginase is another enzyme, which if expressed concomitantly, may strongly compete for L-Arginine, and suppress NO production by iNOS. In the present study, plasma nitrite and arginase levels were measured in VL patients before and after successful drug treatment, endemic and non-endemic healthy donors. We observed significantly lower NO levels in the plasma of VL patients as compared to endemic controls, which improved significantly post-treatment. Significantly elevated arginase activity was also observed in the plasma of VL patients, which may be associated with NO deficiency. VL patients also showed significantly higher levels of IL-10 and TGF-β, which are known to regulate expression of arginase in various immune cells. In vitro studies with human peripheral blood mononuclear cells (PBMCs) further corroborated the role of IL-10 and TGF-β in arginase mediated suppression of NO production. © Copyright © 2021 Kupani, Sharma, Pandey, Kumar, Sundar and Mehrotra.PublicationArticle Anti-interleukin-10 unleashes transcriptional response to leishmanial antigens in visceral leishmaniasis patients(Oxford University Press, 2021) Om Prakash Singh; Genevieve Syn; Susanne Nylén; Christian Engwerda; David Sacks; Mary E. Wilson; Rajiv Kumar; Jaya Chakravarty; Shyam Sundar; Jenefer M. Blackwell; Michaela FakiolaVisceral leishmaniasis (VL; Leishmania donovani) cases produce interferon-γand tumor necrosis factor in response to soluble leishmanial antigen (SLA) in whole-blood assays. Using transcriptional profiling, we demonstrate the impact of interleukin-10 (IL-10), a cytokine implicated in VL, on this response. SLA stimulation identified 28 differentially expressed genes (DEGs), 17/28 in a single network with TNF as hub. SLA plus anti-IL-10 produced 454 DEGs, 292 in a single network with TNF, IFNG, NFKBIA, IL6, and IL1B as hubs in concert with a remarkable chemokine/cytokine storm. Our data demonstrate the singular effect of IL-10 as a potent immune modulator in VL. © 2020 The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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