BITS Faculty Publications
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Item Characterizing the type 6 secretion system (T6SS) of E. cloacae SBP-8 and its role in pathogenesis and bacterial competition(Elsevier, 2023-10) Jha, Prabhat Nath; Marathe, SandhyaDespite the relevance of E. cloacae as an opportunistic pathogen, very little is known about its pathogenicity mechanism and the factors influencing its virulence. The mechanism of E. cloacae pathogenicity appears to be complex and multifactorial, with the presence of different putative virulence factors whose role is still not clear in the development of the disease. In this study, we systematically investigated the role of T6SS (type six secretion system) of E. cloacae SBP-8, an environmental isolate, in eukaryotic and bacterial cell interaction. Analysis of the genome sequence of E. cloacae SBP-8 revealed the presence of sets of genes coding for the expression of one complete T6SS cluster, which is similar to T6SS-1 cluster of E. cloacae ATCC 13047 (clinical isolates). In addition, an Hcp effector protein was detected in the secretome, and this secretion depended on ClpV, an Atpase of T6SS, confirming that strain SBP-8 produces functional T6SS. Deletion of T6SS-associated gene clpV did not induce any significant change in the life span and rate of colonization in C. elegans. No major significant change was observed in the expression profiling of antimicrobial genes (clec-60, clec-85, clec-87 and lys-1) and toll-like receptor (toll-1) gene, involved in stimulating an immune response against the pathogen. No difference in the ability to invade and proliferate in intestinal cells and phagocytosis by macrophages was observed. In addition, we demonstrated that the ability of E. cloacae SBP-8 to out-compete Escherichia coli was reliant upon its T6SS in contact-dependent manner. Our results show that T6SS of the environmental isolates is required for interbacterial competition but not for invasion and proliferation inside host cells.Item Nesting sites of birds and spiders in the semi-arid zone of Rajasthan, India(Current Science, 2018-05) Marathe, SandhyaItem The phylogenomics of CRISPR-Cas system and revelation of its features in Salmonella(Springer Nature, 2020-12) Marathe, SandhyaSalmonellae display intricate evolutionary patterns comprising over 2500 serovars having diverse pathogenic profiles. The acquisition and/or exchange of various virulence factors influences the evolutionary framework. To gain insights into evolution of Salmonella in association with the CRISPR-Cas genes we performed phylogenetic surveillance across strains of 22 Salmonella serovars. The strains differed in their CRISPR1-leader and cas operon features assorting into two main clades, CRISPR1-STY/cas-STY and CRISPR1-STM/cas-STM, comprising majorly typhoidal and non-typhoidal Salmonella serovars respectively. Serovars of these two clades displayed better relatedness, concerning CRISPR1-leader and cas operon, across genera than between themselves. This signifies the acquisition of CRISPR1/Cas region could be through a horizontal gene transfer event owing to the presence of mobile genetic elements flanking CRISPR1 array. Comparison of CRISPR and cas phenograms with that of multilocus sequence typing (MLST) suggests differential evolution of CRISPR/Cas system. As opposed to broad-host-range, the host-specific serovars harbor fewer spacers. Mapping of protospacer sources suggested a partial correlation of spacer content with habitat diversity of the serovars. Some serovars like serovar Enteritidis and Typhimurium that inhabit similar environment/infect similar hosts hardly shared their protospacer sources.Item The Nobel Prize in Chemistry 2020: Celebrating the collaborative efforts leading to a tool (CRISPR-Cas) for rewriting a code of life(Current Science, 2020-11) Marathe, SandhyaThe Nobel Prize in Chemistry 2020 has been awarded to Emmanuelle Charpen- tier, from the Max Planck Unit for the Science of Pathogens, Berlin, Germany and Jennifer A. Doudna, from University of California, Berkeley, USA, for the gene-editing technique known as the CRISPR/Cas9 scissors 1 . For the first time in history, the prize has been awarded within nine years of the discovery and the awardees are an all-female team after Marie Curie (1911) and Dorothy Crowfoot Hodgkin (1967), who are single awardees of the Nobel Prize. No doubt, this discovery has opened up new horizons for therapeutic and biotechno- logical applications. The story of CRISPR/Cas reiterates how research in basic science opens up doors for innovations! A study on arms race between the tiny bacteria and their tiniest enemy, the viruses (Yes! the bac- teria are attacked by viruses, commonly called bacteriophages), has endowed a lot to the world of science. The bacteria have many elegant mechanisms to coun- teract the invading viruses 2 . The CRISPR-Cas system that stands for Clus- tered Regularly Interspaced Short Palindromic Repeats and the CRISPR associated genes is one such mechanism 3,4 . This system stores the memories of the viral attacks as spacers, equally sized signature sequences of the viral genomes, within this CRISPR 3,4 . These spacers are regularly interspaced within the palindromic repeats 3,4Item Epigenetic regulation and autophagy modulation debilitates insulin resistance associated Alzheimer’s disease condition in rats(Springer, 2022-01) Taliyan, Rajeev; Marathe, SandhyaInsulin resistance (IR) and accumulation of amyloid beta (Aβ) oligomers are potential causative factor for Alzheimer’s Disease (AD). Simultaneously, enhanced clearance level of these oligomers through autophagy activation bring novel insights into their therapeutic paradigm. Autophagy activation is negatively correlated with mammalian target of rapamycin (mTOR) and dysregulated mTOR level due to epigenetic alterations can further culminate towards AD pathogenesis. Therefore, in the current study we explored the neuroprotective efficacy of rapamycin (rapa) and vorinostat (vori) in-vitro and in-vivo. Aβ1–42 treated SH-SY5Y cells were exposed to rapa (20 μM) and vori (4 μM) to analyse mRNA expression of amyloid precursor protein (APP), brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), neuronal growth factor (NGF), beclin-1, microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC3), lysosome-associated membrane protein 2 (LAMP2) and microtubule associated protein 2 (MAP2). In order to develop IR condition, rats were fed a high fat diet (HFD) for 8 weeks and then subjected to intracerebroventricular Aβ1–42 administration. Subsequently, their treatment was initiated with rapa (1 mg/kg, i.p.) and vori (50 mg/kg, i.p.) once daily for 28 days. Morris water maze was performed to govern cognitive impairment followed by sacrification for subsequent mRNA, biochemical, western blot and histological estimations. For all the measured parameters, a significant improvement was observed amongst the combination treatment group in contrast to that of the HFD + Aβ1–42 group and that of the groups treated with the drugs alone. Outcomes of the present study thus suggest that combination therapy with rapa and vori provide a prospective therapeutic approach to ameliorate AD symptoms exacerbated by IR.Item Exploring the Neuroprotective Potential of Rosiglitazone Embedded Nanocarrier System on Streptozotocin Induced Mice Model of Alzheimer’s Disease(Springer, 2020-07) Taliyan, Rajeev; Chitkara, Deepak; Marathe, SandhyaAlzheimer’s disease (AD) is a neurodegenerative disorder imposing great threat to an individual’s cognitive capability. Mounting evidence suggests that type 2 diabetes mellitus (T2DM) and AD is closely associated with impaired insulin signalling and glucose metabolism in the brain. Member of the peroxisome proliferator-activated receptor (PPAR) family, especially PPARγ agonists, has been well known for their insulin-sensitizing actions, but due to low water solubility, poor penetration into the brain and associated toxicity limit their use clinically. Therefore, this study has been undertaken to investigate the neuroprotective potential of rosiglitazone embedded nanocarrier system on streptozotocin (STZ) induced mice model of AD. In vitro neuroprotective efficacy of rosiglitazone was determined on SH-SY5Y cells by assessing the messenger ribonulceic acid (mRNA) expression level of genes implicated for cognitive function. AD in mice was developed by intracerebroventricular (ICV) administration of STZ (3 mg/kg) directly into the lateral ventricles of the mice brain. The cognitive parameters and mRNA expression levels were evaluated after treatment with the free form of rosiglitazone as well as its nano-formulated form. It was observed that rosiglitazone elicits neuroprotection on SH-SY5Y cells as evidenced from the upregulation of genes such as cyclic-AMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), and nerve growth factor (NGF), which are involved in cognitive functions. Further, the nano-formulated rosiglitazone induced better neuroprotective efficacy than its free drug treatment on animal model of AD as evidenced by attenuating the behavioural and cognitive abnormalities, oxido-nitrosative stress and pro-inflammatory cytokines, i.e. tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6a) along with improved antioxidant enzymes (superoxide dismutase (SOD), reduced glutathione (GSH), acetylcholine, neuronal density and expression of CREB, BDNF, GDNF and NGF in the hippocampal region. Based on the results, it can be concluded that rosiglitazone nanoformulation exerts strong neuroprotection via increasing the mRNA expression of growth factors and inhibition of oxidative stress, and neuroinflammation eventually prevents neuronal injury in ADItem Modeling the immune response to Salmonella during typhoid(OUP, 2021-05) Marathe, Amol; Marathe, SandhyaSeveral facets of the host immune response to Salmonella infection have been studied independently at great depths to understand the progress and pathogenesis of Salmonella infection. The circumstances under which a Salmonella-infected individual succumbs to an active disease, evolves as a persister or clears the infection are not understood in detail. We have adopted a system-level approach to develop a continuous-time mechanistic model. We considered key interactions of the immune system state variables with Salmonella in the mesenteric lymph node to determine the final disease outcome deterministically and exclusively temporally. The model accurately predicts the disease outcomes and immune response trajectories operational during typhoid. The results of the simulation confirm the role of anti-inflammatory (M2) macrophages as a site for persistence and relapsing infection. Global sensitivity analysis highlights the importance of both bacterial and host attributes in influencing the disease outcome. It also illustrates the importance of robust phagocytic and anti-microbial potential of M1 macrophages and dendritic cells (DCs) in controlling the disease. Finally, we propose therapeutic strategies for both antibiotic-sensitive and antibiotic-resistant strains (such as IFN-γ therapy, DC transfer and phagocytic potential stimulation). We also suggest prevention strategies such as improving the humoral response and macrophage carrying capacity, which could complement current vaccination schemes for enhanced efficiencyItem Vaccine with herbal adjuvant—A better cocktail to combat the infection(Elsiever, 2008-06-25) Marathe, SandhyaCross-talk between microbe and the host makes important contribution to the subsequent course of infection. Edward Jenner and Louis Pasteur—Fathers of vaccinology have wisely thought of combating an infectious bug with the same bug in a non-infectious form. Then on, vaccines have taken a great toll as a prophylactic agent to improve the quality of human life. Vaccines are successful in controlling a substantial portion of the morbidity and mortality in the developing world. Though vaccines against few diseases like small pox, polio and cholera are highly successful, the stories of failed vaccines are far more. An ideal vaccine candidate should be able to elicit the correct response, either Th1 or Th2 to combat the infection along with a strong immune memory. Use of adjuvant in the vaccine preparation is a long standing practice. Despite major advances in our understanding of vaccine adjuvants, both old and new vaccines seem likely to depend on aluminium saltsItem Curcumin! Spicy panacea for all—Friend or foe(Elsiever, 2009-12-11) Marathe, SandhyaTurmeric, an “Indian gold” from Curcuma longa is a household spice in India. The essential component of the turmeric is curcumin and curcuminoids. This spice has managed to leave the household spice bottles and found its place in reputed herbal and medical outlets in beautifully packed bottles. Various pharmaceutical companies have invested in marketing curcumin as compressed tablets, capsules and powder. Various scientific research and clinical trials suggested its use in disorders ranging from Alzheimer's to cancer [1], [2]. Curcumin became panacea for all diseases. Experimental studies using various cell lines and animal models suggested the role of curcumin in possessing anti-inflammatory [3], anti-bacterial [4] and anti-cancer [5] activities. Curcumin have also been shown to lower the cholesterol by increasing the LDL-R [6]. One human clinical trial in Helicobacter pylori (H. pylori) infected patients suggested its role in bringing down the dyspepsia caused by H. pylori. However, curcumin did not clear or decrease the H. pylori burden [7]. The way curcumin signals and modulate the immune functions of various cell types gives an impetus to think that “Can curcumin be given blindly as therapy”? The reactive oxygen and nitrogen species (ROI and RNI) have been always targeted as “evil molecules”, forgetting that the same phagocyte oxidants, in fact are the first line of defense against plethora of intracellular pathogens.Item Detection of microorganisms using biosensors—A smarter way towards detection techniques(Elsiever, 2009-12-15) Marathe, SandhyaAlong with useful microorganisms, there are some that cause potential damage to the animals and plants. Detection and identification of these harmful organisms in a cost and time effective way is a challenge for the researchers. The future of detection methods for microorganisms shall be guided by biosensor, which has already contributed enormously in sensing and detection technology. Here, we aim to review the use of various biosensors, developed by integrating the biological and physicochemical/mechanical properties (of tranducers), which can have enormous implication in healthcare, food, agriculture and biodefence. We have also highlighted the ways to improve the functioning of the biosensor.
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