Browsing by Author "Manish Gupta"

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A combined subunit vaccine comprising BP26, Omp25 and L7/L12 against brucellosis
(Oxford University Press, 2019) Sonal Gupta; Damini Singh; Manish Gupta; Rakesh Bhatnagar
The current vaccines against brucellosis, namely Brucella abortus strains 19 and RB51, prevent infection in animals but pose potential risks like virulence and attenuation reversal. In this milieu, although subunit vaccination using a single potent immunogen of B. abortus, e.g. BP26 or Omp25 or L7/L12 etc., appears as a safer alternative, nonetheless it confers inadequate protection against the zoonosis compared to attenuated vaccines. Hence, we have investigated the prophylactic potential of a combined subunit vaccine (CSV) comprising the BP26, Omp25 and L7/L12 antigens of B. abortus, in mice model. Sera obtained from CSV immunized mice groups showed heightened IgG titers against all the three components and exhibited specificity upon immunoblotting, reiterating their authenticity. Further, the IgG1/IgG2a ratio obtained against each antigen revealed a predominant Th2 immune response in CSV immunized mice group. However, on assessing the levels of Th1-dependent (IFN-γ and TNF-α) and Th2-dependent (IL-4 and IL-10) cytokines in different formulations, prominent IFN-γ levels were elicited in CSV immunized mice. Further, upon infection with virulent B. abortus 544, the combined subunit vaccinated mice displayed superior degree of protection (Log10 reduction) than the individual vaccines; however, B. abortus S19 showed the highest protection. Altogether, this study suggests that co-immunization of three B. abortus immunogens as a CSV complements and triggers a mixed Th1/Th2 immune response leading to superior degree of protection against pathogenic B. abortus 544 infection. © FEMS 2020.
Cross-serotype protection against group A Streptococcal infections induced by immunization with SPy_2191
(Nature Research, 2020) Pooja Sanduja; Manish Gupta; Vikas Kumar Somani; Vikas Yadav; Meenakshi Dua; Emanuel Hanski; Abhinay Sharma; Rakesh Bhatnagar; Atul Kumar Johri
Group A Streptococcus (GAS) infection causes a range of diseases, but vaccine development is hampered by the high number of serotypes. Here, using reverse vaccinology the authors identify SPy_2191 as a cross-protective vaccine candidate. From 18 initially identified surface proteins, only SPy_2191 is conserved, surface-exposed and inhibits both GAS adhesion and invasion. SPy_2191 immunization in mice generates bactericidal antibodies resulting in opsonophagocytic killing of prevalent and invasive GAS serotypes of different geographical regions, including M1 and M49 (India), M3.1 (Israel), M1 (UK) and M1 (USA). Resident splenocytes show higher interferon-γ and tumor necrosis factor-α secretion upon antigen re-stimulation, suggesting activation of cell-mediated immunity. SPy_2191 immunization significantly reduces streptococcal load in the organs and confers ~76-92% protection upon challenge with invasive GAS serotypes. Further, it significantly suppresses GAS pharyngeal colonization in mice mucosal infection model. Our findings suggest that SPy_2191 can act as a universal vaccine candidate against GAS infections. © 2020, The Author(s).
Does psychological climate affect task and contextual performance through affective commitment? Evidence from public sector companies
(Emerald Publishing, 2020) Ram Shankar Uraon; Manish Gupta
Purpose: This paper has two main purposes. One purpose is to examine the mediating role of affective commitment in the relationship between psychological climate and contextual and task performance. Another purpose is to conceptualize and measure the psychological climate. Design/methodology/approach: Data were analyzed using a sample of 514 employees working in 12 public sector companies in India. Partial least squares (PLS) technique was used to test the proposed research framework. Findings: The results of this study revealed that affective commitment has a mediating role in the relationship between psychological climate and contextual performance as well as between psychological climate task performance. Research limitations/implications: The findings of this study augment the theory of psychological climate by suggesting that individuals perceiving high a psychological climate are likely to have the high affective commitment that ultimately leads to higher performance. Practical implications: Public sector companies are encouraged to provide a favorable psychological climate that can emotionally commit the employees to perform well. Originality/value: This study is one of its kinds to overcome the limitations of the earlier studies such as in examining the effect of higher-order psychological climate on task and contextual performances. © 2020, Emerald Publishing Limited.
Importance of cell wall-associated poly-α-l-glutamine in the biology of pathogenic mycobacteria
(Springer Singapore, 2019) Rajni Garg; Rajesh Mani; Manish Gupta; Deeksha Tripathi; Harish Chandra; Rakesh Bhatnagar; Nirupama Banerjee
Mycobacterium tuberculosis (Mtb), the formidable scourge known to mankind since ancient times, has remained untamed despite vigorous scientific research in the field. In the last several decades, significant advances have been made to study this pathogen; however, a lot more remains in the realm of unknown. The complex and unique cell wall of the bacterium is a major factor contributing to the unrestrained success of the pathogen in infecting millions around the world. Since the discovery of this bacterium, numerous studies have attempted to unravel the complexities of mycobacterial cell envelop to characterize individual constituents and their importance in pathobiology of Mtb. Major components of the cell envelop of mycobacteria such as lipid-linked polysaccharides-lipoarabinomannan (LAM), dimycolyl trehalose (cord factor), sulfolipids, and mycolyl-arabinogalactan-peptidoglycan (mAGP) complex have been investigated extensively. However, a lesser known molecule, poly-α-L-glutamine/glutamate (PLG), that constitutes ~10% of dry weight of cell wall has not attracted as much attention. As early as 1990, Hirschfield et al. isolated PLG as insoluble material and showed its association with the Mtb cell wall. In the last few years, our group has been working to identify enzymes that may play a role in the synthesis/assembly and localization of this polymer in the cell wall of mycobacteria. Our recently published work has shown that PLG by itself is weakly immunogenic in mice, but when combined with protein antigens, it can stimulate different arms of the T helper-mediated responses, demonstrating its potential to act as an adjuvant (Mani et al. 2018). © Springer Nature Singapore Pte Ltd. 2019.
Structure-based drug repurposing to inhibit the DNA gyrase of Mycobacterium tuberculosis
(Portland Press Ltd, 2020) G.L. Balasubramani; Rinky Rajput; Manish Gupta; Pradeep Dahiya; Jitendra K. Thakur; Rakesh Bhatnagar; Abhinav Grover
Drug repurposing is an alternative avenue for identifying new drugs to treat tuberculosis (TB). Despite the broad-range of anti-tubercular drugs, the emergence of multi-drug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) H37Rv, as well as the significant death toll globally, necessitates the development of new and effective drugs to treat TB. In this study, we have employed a drug repurposing approach to address this drug resistance problem by screening the drugbank database to identify novel inhibitors of the Mtb target enzyme, DNA gyrase. The compounds were screened against the ATPase domain of the gyrase B subunit (MtbGyrB47), and the docking results showed that echinacoside, doxorubicin, epirubicin, and idarubicin possess high binding affinities against MtbGyrB47. Comprehensive assessment using fluorescence spectroscopy, surface plasmon resonance spectroscopy (SPR), and circular dichroism (CD) titration studies revealed echinacoside as a potent binder of MtbGyrB47. Furthermore, ATPase, and DNA supercoiling assays exhibited an IC50 values of 2.1-4.7 mM for echinacoside, doxorubicin, epirubicin, and idarubicin. Among these compounds, the least MIC90 of 6.3 and 12 μM were observed for epirubicin and echinacoside, respectively, against Mtb. Our findings indicate that echinacoside and epirubicin targets mycobacterial DNA gyrase, inhibit its catalytic cycle, and retard mycobacterium growth. Further, these compounds exhibit potential scaffolds for optimizing novel anti-mycobacterial agents that can act on drug-resistant strains. © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society