Browsing by Author "Awnish Kumar"

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A molecular signature for IL-10–producing Th1 cells in protozoan parasitic diseases
(American Society for Clinical Investigation, 2023) Chelsea L. Edwards; Jessica A. Engel; Fabian de Labastida Rivera; Susanna S. Ng; Dillon Corvino; Marcela Montes de Oca; Teija C.M. Frame; Shashi Bhushan Chauhan; Siddharth Sankar Singh; Awnish Kumar; Yulin Wang; Jinrui Na; Pam Mukhopadhyay; Jason S. Lee; Susanne Nylen; Shyam Sundar; Rajiv Kumar; Christian R. Engwerda
Control of visceral leishmaniasis (VL) depends on proinflammatory Th1 cells that activate infected tissue macrophages to kill resident intracellular parasites. However, proinflammatory cytokines produced by Th1 cells can damage tissues and require tight regulation. Th1 cell IL-10 production is an important cell–autologous mechanism to prevent such damage. However, IL-10–producing Th1 (type 1 regulatory; Tr1) cells can also delay control of parasites and the generation of immunity following drug treatment or vaccination. To identify molecules to target in order to alter the balance between Th1 and Tr1 cells for improved antiparasitic immunity, we compared the molecular and phenotypic profiles of Th1 and Tr1 cells in experimental VL caused by Leishmania donovani infection of C57BL/6J mice. We also identified a shared Tr1 cell protozoan signature by comparing the transcriptional profiles of Tr1 cells from mice with experimental VL and malaria. We identified LAG3 as an important coinhibitory receptor in patients with VL and experimental VL, and we reveal tissue-specific heterogeneity of coinhibitory receptor expression by Tr1 cells. We also discovered a role for the transcription factor Pbx1 in suppressing CD4+ T cell cytokine production. This work provides insights into the development and function of CD4+ T cells during protozoan parasitic infections and identifies key immunoregulatory molecules. © 2023, Edwards et al.
Advancements and Challenges in Developing Malaria Vaccines: Targeting Multiple Stages of the Parasite Life Cycle
(American Chemical Society, 2023) None Rajneesh; Rahul Tiwari; Vishal K. Singh; Awnish Kumar; Rohit P. Gupta; Akhilesh K. Singh; Vibhav Gautam; Rajiv Kumar
Malaria, caused by Plasmodium species, remains a major global health concern, causing millions of deaths annually. While the introduction of the RTS,S vaccine has shown promise, there is a pressing need for more effective vaccines due to the emergence of drug-resistant parasites and insecticide-resistant vectors. However, the complex life cycle and genetic diversity of the parasite, technical obstacles, limited funding, and the impact of the 2019 pandemic have hindered progress in malaria vaccine development. This review focuses on advancements in malaria vaccine development, particularly the ongoing clinical trials targeting antigens from different stages of the Plasmodium life cycle. Additionally, we discuss the rationale, strategies, and challenges associated with vaccine design, aiming to enhance the immune response and protective efficacy of vaccine candidates. A cost-effective and multistage vaccine could hold the key to controlling and eradicating malaria. © 2023 American Chemical Society.
Amphiregulin in cellular physiology, health, and disease: Potential use as a biomarker and therapeutic target
(John Wiley and Sons Inc, 2022) Siddharth S. Singh; Shashi B. Chauhan; Awnish Kumar; Shashi Kumar; Christian R. Engwerda; Shyam Sundar; Rajiv Kumar
Amphiregulin (AREG), which acts as one of the ligands for epidermal receptor growth factor receptor (EGFR), plays a crucial role in tissue repair, inflammation, and immunity. AREG is synthesized as membrane-anchored pre-protein, and is excreted after proteolytic cleavage, and serves as an autocrine or paracrine factor. After engagement with the EGFR, AREG triggers a cascade of signaling events required for many cellular physiological processes including metabolism, cell cycle, and proliferation. Under different inflammatory and pathogenic conditions, AREG is expressed by various activated immune cells that orchestrate both tolerance and host resistance mechanisms. Several factors including xenobiotics, cytokines, and inflammatory lipids have been shown to trigger AREG gene expression and release. In this review, we discuss the structure, function, and regulation of AREG, its role in tissue repair, inflammation, and homeostasis as well as the potential of AREG as a biomarker and therapeutic target. © 2021 Wiley Periodicals LLC
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 Kumar
Leishmaniasis, 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.
Emerging role of γδ T cells in protozoan infection and their potential clinical application
(Elsevier B.V., 2022) Awnish Kumar; Bhawana Singh; Rahul Tiwari; Vishal Kumar Singh; Siddharth Sankar Singh; Shyam Sundar; Rajiv Kumar
γδ T cells are thymus derived heterogeneous and unconventional T- lymphocyte expressing TCR γ (V γ9) and TCRδ (Vδ2) chain and play an important role in connecting innate and adaptive armaments of immune response. These cells can recognize wide ranges of antigens even without involvement of major histocompatibility complex and exert their biological functions by cytotoxicity or activating various types of immune cells. In recent past, γδ T cells have emerged as an important player during protozoa infection and rapidly expand after exposure with them. They have also been widely studied in vaccine induced immune response against many bacterial and protozoan infections with improved clinical outcome. In this review, we will discuss the various roles of γδ T cells in immunity against malaria and leishmaniasis, the two important protozoan diseases causing significant mortality and morbidity throughout the world. © 2022
Evaluation of blood based quantitative PCR as a molecular diagnostic tool for post kala-azar dermal leishmaniasis (PKDL)
(Springer Science and Business Media B.V., 2024) Awnish Kumar; Vishal K. Singh; Prasoon Madhukar; Rahul Tiwari; Ritirupa Roy; Rajneesh; Sanjana Mehrotra; Shyam Sundar; Rajiv Kumar
Background: Post kala-azar dermal leishmaniasis (PKDL) is a consequential dermal manifestation of visceral leishmaniasis (VL), serving as a parasite reservoir. The traditional diagnostic approach, which requires an invasive skin biopsy is associated with inherent risks and necessitates skilled healthcare practitioners in sterile settings. There is a critical need for a rapid, less invasive method for Leishmania detection. The main objective of this study was to evaluate and compare the diagnostic efficacy of PCR and qPCR in detecting PKDL, utilizing both skin and blood samples and to assess the utility of blood samples for molecular diagnosis. Methods and results: 73 individuals exhibiting clinical symptoms of PKDL and who had tested positive for rK39 rapid diagnostic test (RDT) were enrolled in this study. For the diagnosis of PKDL, both PCR and real-time quantitative PCR (qPCR), employing SYBR Green and TaqMan assays, were performed on blood and skin matched samples. qPCR results using both TaqMan and SYBR Green assay, indicated higher parasite loads in the skin compared to blood, as evident by the Ct values. Importantly, when blood samples were used for PKDL diagnosis by qPCR, an encouraging sensitivity of 69.35% (TaqMan assay) and 79.36% (SYBR Green) were obtained, compared to 8.2% with conventional PCR. Conclusion: The findings of the study suggest the potential utility of blood for molecular diagnosis by qPCR, offering a less invasive alternative to skin biopsies in field setting for the early detection of parasitaemia in PKDL patients and effective management and control of the disease. © The Author(s), under exclusive licence to Springer Nature B.V. 2024.
Exploring Metabolic and Immunological Biomarkers for Oral Squamous Cell Carcinoma: Potential Targets for Precision Therapy
(Multidisciplinary Digital Publishing Institute (MDPI), 2025) Rajneesh; Rahul Tiwari; Vishal K. Singh; Awnish Kumar; Sanjana Mehrotra; Vibhav Gautam; J. F. Neville; Vyomika Bansal; Rajiv Pathak; Akhilesh Kumar Singh; Rajiv Kumar
Oral squamous cell carcinoma (OSCC) is a malignant neoplasm of the oral epithelium that constitutes majority of oral cancers and is strongly associated with risk factors such as tobacco use and genetic alterations. Mortality rates for OSCC are high because many cases are misdiagnosed or identified at later stages, and treatment options are limited with high recurrence. Therefore, there is an urgent need for improved diagnostic and therapeutic strategies. OSCC tumor cells, like those in other solid malignancies, exhibit significant alterations in metabolic pathways and the immune microenvironment. These changes can serve as valuable biomarkers for early detection and as targets for innovative treatment strategies. This review summarizes the current understanding of metabolic and immunological biomarkers that are either currently in use for OSCC or are in different phases of clinical trials. © 2025 by the authors.
Field-friendly anti-PGL-I serosurvey in children to monitor Mycobacterium leprae transmission in Bihar, India
(Frontiers Media SA, 2023) Louise Pierneef; Paritosh Malaviya; Anouk van Hooij; Shyam Sundar; Abhishek Kumar Singh; Rajiv Kumar; Danielle de Jong; Maaike Meuldijk; Awnish Kumar; Zijie Zhou; Kristien Cloots; Paul Corstjens; Epco Hasker; Annemieke Geluk
Background: It has been amply described that levels of IgM antibodies against Mycobacterium leprae (M. leprae) phenolic glycolipid I (PGL-I) correlate strongly with the bacterial load in an infected individual. These findings have generated the concept of using seropositivity for antibodies against M. leprae PGL-I as an indicator of the proportion of the population that has been infected. Although anti-PGL-I IgM levels provide information on whether an individual has ever been infected, their presence cannot discriminate between recent and past infections. Since infection in (young) children by definition indicates recent transmission, we piloted the feasibility of assessment of anti-PGL-I IgM seroprevalence among children in a leprosy endemic area in India as a proxy for recent M. leprae transmission. Material and methods: A serosurvey for anti-PGL-I IgM antibodies among children in highly leprosy endemic villages in Bihar, India, was performed, applying the quantitative anti-PGL-I UCP-LFA cassette combined with low-invasive, small-volume fingerstick blood (FSB). Results: Local staff obtained FSB of 1,857 children (age 3–11 years) living in 12 leprosy endemic villages in Bihar; of these, 215 children (11.58%) were seropositive for anti-PGL-I IgM. Conclusion: The anti-PGL-I seroprevalence level of 11.58% among children corresponds with the seroprevalence levels described in studies in other leprosy endemic areas over the past decades where no prophylactic interventions have taken place. The anti-PGL-I UCP-LFA was found to be a low-complexity tool that could be practically combined with serosurveys and was well-accepted by both healthcare staff and the population. On route to leprosy elimination, quantitative anti-PGL-I serology in young children holds promise as a strategy to monitor recent M. leprae transmission in an area. Copyright © 2023 Pierneef, Malaviya, van Hooij, Sundar, Singh, Kumar, de Jong, Meuldijk, Kumar, Zhou, Cloots, Corstjens, Hasker and Geluk.
Infection, immunity, and vaccine development
(Elsevier, 2022) Bhawana Singh; Awnish Kumar; Rahul Tiwari; Shashi Bhushan Chauhan; Om Prakash Singh; Santosh K. Singh; Vibhav Gautam; Shyam Sundar; Rajiv Kumar
Vaccination has emerged as one of the cheapest and most important healthcare interventions, saving millions of lives in both developed and developing countries. Currently, the development of drug-resistant pathogen strains and the emergence of new human pathogens due to changes in climate and human behavior have challenged vaccinologists to develop novel strategies for the development of new and effective vaccines. While most classical vaccines were developed pragmatically without a precise understanding about how they elicit immune responses and provide protection, current advancements in the fields of immunology, microbiology, genetics, molecular biology, and host-pathogen interactions have opened new opportunities for modern vaccine development with greater impact. This impact must not only be directed against established and newly emerging pathogens but should also provide protection for immune-compromised and elderly individuals. In this chapter, we will discuss host immune responses against pathogens, basic concepts about vaccine immunology and how they mediate protection against infectious agents. We will not discuss vaccine development strategies in detail, but only overview the key consideration in vaccine development programs. © 2022 Elsevier Inc. All rights reserved.
MHC tetramer technology: Exploring T cell biology in health and disease
(Academic Press Inc., 2024) Rahul Tiwari; Vishal Kumar Singh; Rajneesh; Awnish Kumar; Vibhav Gautam; Rajiv Kumar
Major histocompatibility complex (MHC) tetramers stand as formidable tools within T cell biology, facilitating the exploration and comprehension of immune responses. These artificial molecules, comprising four bound MHC molecules, typically with a specified peptide and a fluorescent label, play a pivotal role in characterizing T cell subsets, monitoring clonal expansion, and unraveling T cell dynamics during responses to infections or immunotherapies. Beyond their applications in T cell biology, MHC tetramers prove valuable in investigating a spectrum of diseases such as infectious diseases, autoimmune disorders, and cancers. Their instrumental role extends to vaccine research and development. Notably, when appropriately configured, tetramers transcend T cell biology research and find utility in exploring natural killer T cells and contributing to specific T cell clonal deletions. © 2024
MicroRNAs-mediated regulation of immune responses in parasitic infection
(Elsevier, 2024) Ritirupa Roy; Prasoon Madhukar; Vishal Kumar Singh; Rahul Tiwari; Awnish Kumar; Rajneesh; Madhukar Rai; Vibhav Gautam; Shyam Sundar; Rajiv Kumar
Leishmaniasis is a group of diseases that predominantly affect impoverished individuals in developing regions. Recent research has highlighted the significant role of microRNAs (miRNAs), small noncoding RNA molecules, in regulating gene expression and contributing to disease pathogenesis in leishmaniasis. Understanding the intricate miRNA-mediated interactions provides valuable insights into the underlying mechanisms of leishmaniasis and facilitates the development of targeted interventions. Moreover, miRNAs demonstrate altered expression levels, and their presence in the bloodstream enables noninvasive detection, making them promising biomarker candidates for diagnosis and prognosis. This chapter focuses on the role of miRNAs in regulating the immune response during leishmania infection, emphasizing their potential as both biomarkers and therapeutic targets. © 2024 Elsevier Inc. All rights reserved.
Nanomedicine in Cardiovascular Diseases: Diagnostic and Therapeutic Innovations for Better Health
(Springer Science and Business Media B.V., 2024) Prasoon Madhukar; Vishal Kumar Singh; Shashi Bhushan Chauhan; Rahul Tiwari; Awnish Kumar; Rajneesh; Rajiv Kumar
Cardiovascular diseases (CVDs) are a major cause of global mortality, responsible for approximately 17.9 million deaths in 2019 and 20.5 million deaths in 2021. Limited access to specialised testing, especially for marginalised population, complicate the diagnosis of cardiovascular conditions. Disparities in treatment, sub-optimal pharmaceuticals, toxicity from conventional drugs, diagnostic errors, and the underutilization of non-invasive diagnostic methods contribute to adverse outcomes. Additionally, cost and insurance barriers hinder access to necessary tests, delaying diagnosis and treatment. Therefore, there is an urgent need for improved therapies for CVDs. Additionally, cost and insurance barriers hinder access to necessary tests, delaying diagnosis and treatment. Therefore, there is an urgent need for improved therapies for CVDs. Nanotechnology, which involves the precise control and manipulation of materials at the atomic and molecular levels, shows promise in addressing cardiovascular diseases. Nanoparticles, with their unique properties such as ultra-small size, tunable physicochemical characteristics, and biocompatibility, offer potential for targeted drug delivery. Nanoparticle-based drug delivery systems can enhance therapeutic effectiveness, prolong drug action, improve drug absorption, target specific areas passively or actively, reduce drug resistance, and minimize adverse drug reactions. This chapter comprehensively examines the use of nanoparticle-based diagnostic methods, targeting strategies, and therapeutic interventions for cardiovascular diseases, providing a thorough explanation of the fundamental principles and key considerations in this field. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2024.
Nanotechnology-Based Strategies in Parasitic Disease Management: From Prevention to Diagnosis and Treatment
(American Chemical Society, 2023) Rahul Tiwari; Rohit P. Gupta; Vishal K. Singh; Awnish Kumar; None Rajneesh; Prasoon Madhukar; Shyam Sundar; Vibhav Gautam; Rajiv Kumar
Parasitic infections are a major global health issue causing significant mortality and morbidity. Despite substantial advances in the diagnostics and treatment of these diseases, the currently available options fall far short of expectations. From diagnosis and treatment to prevention and control, nanotechnology-based techniques show promise as an alternative approach. Nanoparticles can be designed with specific properties to target parasites and deliver antiparasitic medications and vaccines. Nanoparticles such as liposomes, nanosuspensions, polymer-based nanoparticles, and solid lipid nanoparticles have been shown to overcome limitations such as limited bioavailability, poor cellular permeability, nonspecific distribution, and rapid drug elimination from the body. These nanoparticles also serve as nanobiosensors for the early detection and treatment of these diseases. This review aims to summarize the potential applications of nanoparticles in the prevention, diagnosis, and treatment of parasitic diseases such as leishmaniasis, malaria, and trypanosomiasis. It also discusses the advantages and disadvantages of these applications and their market values and highlights the need for further research in this field. © 2023 The Authors. Published by American Chemical Society.
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 Kumar
Visceral 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.
The circulating plasma microRNA signature in human visceral leishmaniasis
(American Society for Microbiology, 2025) Ritirupa Roy; Cinthia L. Hudachek; Shashi Bhushan Chauhan; Shashi Kumar; Awnish Kumar; Bayan Sudan Zhanbolat; Madhukar Rai; Rajiv Kumar; Santhanam Sundar; Mary E. Wilson
Visceral leishmaniasis (VL) is a vector-borne disease caused by the obligate intracellular protozoan Leishmania donovani in India. VL can be complicated by post-kala-azar dermal leishmaniasis (PKDL), a macular or nodular rash that develops in 10%-20% of patients after treatment of VL in India. Patients with PKDL are infectious to sand flies,promoting further transmission of the parasite. MicroRNAs (miRNAs) are 18-25 nt, non-coding RNAs that simultaneously regulate the expression of several or many target transcripts. This study was based on the hypothesis that the host response to L. donovani is modifiedby distinct sets of miRNAs in VL or PKDL and that these might differfrom healthy controls. We investigated this hypothesis using a NanoString panel to profilethe miRNAs expressed in the plasma of patients with VL or PKDL diagnosed at a hospital in Bihar, India. We compared these to plasma microRNAs of healthy control individuals from the same endemic villages. miRNAs hsa-miR-223-3p, hsa-miR-191-5p, hsa-miR-23a-3p, and hsa-1285-5p were significantlyhigher in the plasma samples from patients with VL compared to either PKDL or endemic controls. Prediction programs highlighted potential mRNA targeted by these miRNAs, among which we verifiedthe down-modulation of several transcripts belonging to the NFκB and NLRP3 inflammasomepathways in circulating leukocytes of VL patients. By contrast, miRNA patterns in subjects with PKDL were similar to control subjects, possibly suggesting that the pathogenic immune response during PKDL is primarily localized in the skin. © 2025 American Society for Microbiology. All rights reserved.
The development and maintenance of immunity against visceral leishmaniasis
(Frontiers Media SA, 2024) Rahul Tiwari; Awnish Kumar; Vishal Kumar Singh; Rajneesh; Shashi Bhushan Chauhan; Shyam Sundar; Susanne Nylén; Christian Engwerda; Rajiv Kumar
Understanding the development and maintenance of immunological memory is important for efforts to eliminate parasitic diseases like leishmaniasis. Leishmaniasis encompasses a range of pathologies, resulting from infection with protozoan parasites belonging to the subgenera Leishmania and Viannia of the genus Leishmania. A striking feature of these infections is that natural or drug-mediated cure of infection generally confers life-long protection against disease. The generation of protective T cell responses are necessary to control Leishmania infections. CD4+ T helper (Th) cells orchestrate immune responses in leishmaniasis and IFNγ+ Tbet+ CD4+ T (Th1) cells are required for the activation of phagocytes to kill captured or resident parasites, while other Th cell subset, including FoxP3+ natural regulatory T cells and Th2 cells can promote disease progression by suppressing the activities of Th1 cells. Upon resolution of a primary Leishmania infection, different subsets of CD4+ T cells, including tissue-resident memory T cells, effector memory T cells, central memory T cells, and short-lived effector T cells, help to confer resistance against reinfection. To maintain long-term protective Leishmania-specific CD4+ T cells responses, it is believed that persistent parasites or re-exposure to parasites at regular intervals is required (concomitant immunity). Despite the advances in our understanding about the immune responses during leishmaniasis, the generation of long-lasting protective immunity via vaccination has yet to be achieved. In this review, we summarize our current understanding about the formation and maintenance of immunological memory and control of leishmaniasis at the individual and population level. We will focus on Indian visceral leishmaniasis and discuss T cell responses that contribute to susceptibility to leishmaniasis, parasite persistence in populations and the environment, as well as describing advances in the development of leishmaniasis vaccines aimed at inducing protective CD4+ T cell responses. Copyright © 2024 Tiwari, Kumar, Singh, Rajneesh, Chauhan, Sundar, Nylén, Engwerda and Kumar.