Multi-organ single-cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases Sandra Lilja, Xinxiu Li, Martin Smelik, Eun Jung Lee, Joseph Loscalzo, Pratheek Bellur Marthanda, Lang Hu, Mattias Magnusson, Oleg Sysoev, Huan Zhang, Yelin Zhao, Christopher Sjöwall, Danuta Gawel, Hui Wang, Mikael Benson Cell Reports Medicine, 2023 Prioritization of disease mechanisms, biomarkers, and drug targets in immune-mediated inflammatory diseases (IMIDs) is complicated by altered interactions between thousands of genes. Our multi-organ single-cell RNA sequencing of a mouse IMID model, namely collagen-induced arthritis, shows highly complex and heterogeneous expression changes in all analyzed organs, even though only joints showed signs of inflammation. We organized those into a multi-organ multicellular disease model, which shows predicted molecular interactions within and between organs. That model supports that inflammation is switched on or off by altered balance between pro- and anti-inflammatory upstream regulators (URs) and downstream pathways. Meta-analyses of human IMIDs show a similar, but graded, on/off switch system. This system has the potential to prioritize, diagnose, and treat optimal combinations of URs on the levels of IMIDs, subgroups, and individual patients. That potential is supported by UR analyses in more than 600 sera from patients with systemic lupus erythematosus.
VIPER regulates naive T cell activation and effector responses: Implication in TLR4 associated acute stage T cell responses Subhransu Sekhar Sahoo, Belluru M. Pratheek, Vikram S. Meena, Tapas Kumar Nayak, P. Sanjai Kumar, Saumya Bandyopadhyay, Prasanta Kumar Maiti, Subhasis Chattopadhyay Scientific Reports, 2018 Naive T cells are known to express the modest level of TLR4 while it is known to go down during TCR activation. However, information towards the requirement of TLR4 signaling during TCR or mitogenic activation of naive wild-type T cells remains scanty. Here we have investigated the endogenous functional expression of TLR4 in naive mice T cells during TCR and mitogenic stimulation in presence of VIPER peptide (VP), an established inhibitor of TLR4 signaling. As expected we found that TLR4 expression goes down during TCR and mitogenic activation. Interestingly, we observed that VP treatment restores TLR4 expression on those activated T cells. Moreover, VP was found to regulate such activation of naive T cell as evident by reduction of CD25, CD69 expression, effector cytokines (IL-2, IFN-γ, TNF) production, T cell proliferation and down-regulation of T cell activation-dependent Fas (CD95), FasL (CD95L) expression. Together, our current observation highlights a possible requirement of TLR4 responses in T cells, which might have possible implication towards the pathogenic acute phase activation of naive T cells.
Functional expression of TRPV channels in T cells and their implications in immune regulation Rakesh K. Majhi, Subhransu S. Sahoo, Manoj Yadav, Belluru M. Pratheek, Subhasis Chattopadhyay, Chandan Goswami FEBS Journal, 2015 The importance of Ca2+signalling and temperature in the context of T cell activation is well known. However, the molecular identities of key players involved in such critical regulations are still unknown. In this work we explored the endogenous expression of transient receptor potential vanilloid (TRPV) channels, a group of thermosensitive and non‐selective cation channels, in T cells. Using flow cytometry and confocal microscopy, we demonstrate that members belonging to theTRPVsubfamily are expressed endogenously in the human T cell line Jurkat, in primary human T cells and in primary murine splenic T cells. We also demonstrate thatTRPV1‐ andTRPV4‐specific agonists, namely resiniferatoxin and 4α‐phorbol‐12,13‐didecanoate, can cause Ca2+influx in T cells. Moreover, our results show that expression of these channels can be upregulated in T cells during concanavalin A‐driven mitogenic and anti‐CD3/CD28 stimulated TCR activation of T cells. By specific blocking ofTRPV1 andTRPV4 channels, we found that theseTRPVinhibitors may regulate mitogenic and T cell receptor mediated T cell activation and effector cytokine(s) production by suppressing tumour necrosis factor, interleukin‐2 and interferon‐γ release. These results may have broad implications in the context of cell‐mediated immunity, especially T cell responses and their regulations, neuro‐immune interactions and molecular understanding of channelopathies.
Regulation of Noxa-mediated apoptosis in Helicobacter pylori-infected gastric epithelial cells Suvasmita Rath, Lopamudra Das, Shrikant Babanrao Kokate, B. M. Pratheek, Subhasis Chattopadhyay, Chandan Goswami, Ranajoy Chattopadhyay, Sheila Eileen Crowe, Asima Bhattacharyya FASEB Journal, 2015 Helicobacter pylori induces the antiapoptotic protein myeloid cell leukemia 1 (Mcl1) in human gastric epithelial cells (GECs). Apoptosis of oncogenic protein Mcl1‐expressing cells is mainly regulated by Noxa‐mediated degradation of Mcl1. We wanted to elucidate the status of Noxa in H. pylori ‐infected GECs. For this, various GECs such as AGS, MKN45, and KATO III were either infected with H. pylori or left uninfected. The effect of infection was examined by immunoblotting, immunoprecipitation, chromatin immunoprecipitation assay, in vitro binding assay, flow cytometry, and confocal microscopy. Infected GECs, surgical samples collected from patients with gastric adenocarcinoma as well as biopsy samples from patients infected with H. pylori showed significant up‐regulation of both Mcl1 and Noxa compared with noninfected samples. Coexistence of Mcl1 and Noxa was indicative of an impaired Mcl‐Noxa interaction. We proved that Noxa was phosphorylated at Ser 13 residue by JNK in infected GECs, which caused cytoplasmic retention of Noxa. JNK inhibition enhanced Mcl1‐Noxa interaction in the mitochondrial fraction of infected cells, whereas overexpression of nonphosphorylatable Noxa resulted in enhanced mitochondria‐mediated apoptosis in the infected epithelium. Because phosphorylation‐dephosphorylation can regulate the apoptotic function of Noxa, this could be a potential target molecule for future treatment approaches for H. pylori ‐induced gastric cancer.—Rath, S., Das, L., Kokate, S. B., Pratheek, B. M., Chattopadhyay, S., Goswami, C., Chattopadhyay, R., Crowe, S. E., Bhattacharyya, A., Regulation of Noxa‐mediated apoptosis in Helicobacter pylori –infected gastric epithelial cells. FASEB J. 29, 796–806 (2015). www.fasebj.org
Induction of apoptosis by Fe(salen)Cl through caspase-dependent pathway specifically in tumor cells Nitika Pradhan, B.M. Pratheek, Antara Garai, Ashutosh Kumar, Vikram S. Meena, Shyamasree Ghosh, Sujay Singh, Shikha Kumari, T.K. Chandrashekar, Chandan Goswami, Subhasis Chattopadhyay, Sanjib Kar, Prasanta K. Maiti Cell Biology International, 2014 Iron‐based compounds possess the capability of inducing cell death due to their reactivity with oxidant molecules, but their specificity towards cancer cells and the mechanism of action are hitherto less investigated. A Fe(salen)Cl derivative has been synthesized that remains active in monomer form. The efficacy of this compound as an anti‐tumor agent has been investigated in mouse and human leukemia cell lines. Fe(salen)Cl induces cell death specifically in tumor cells and not in primary cells. Mouse and human T‐cell leukemia cell lines, EL4 and Jurkat cells are found to be susceptible to Fe(salen)Cl and undergo apoptosis, but normal mouse spleen cells and human peripheral blood mononuclear cells (PBMC) remain largely unaffected by Fe(salen)Cl. Fe(salen)Cl treated tumor cells show significantly higher expression level of cytochrome c that might have triggered the cascade of reactions leading to apoptosis in cancer cells. A significant loss of mitochondrial membrane potential upon Fe(salen)Cl treatment suggests that Fe(salen)Cl induces apoptosis by disrupting mitochondrial membrane potential and homeostasis, leading to cytotoxity. We also established that apoptosis in the Fe(salen)Cl‐treated tumor cells is mediated through caspase‐dependent pathway. This is the first report demonstrating that Fe(salen)Cl can specifically target the tumor cells, leaving the primary cells least affected, indicating an excellent potential for this compound to emerge as a next‐generation anti‐tumor drug.
Heat shock protein 90 positively regulates Chikungunya virus replication by stabilizing viral non-structural protein nsP2 during infection Indrani Das, Itishree Basantray, Prabhudutta Mamidi, Tapas K. Nayak, Pratheek B. M., Subhasis Chattopadhyay, Soma Chattopadhyay Plos One, 2014 BACKGROUND: The high morbidity and socio-economic loss associated with the recent massive global outbreak of Chikungunya virus (CHIKV) emphasize the need to understand the biology of the virus for developing effective antiviral therapies. METHODS AND FINDINGS: In this study, an attempt was made to understand the molecular mechanism involved in Heat shock protein 90 (Hsp90) mediated regulation of CHIKV infection in mammalian cells using CHIKV prototype strain (S 27) and Indian outbreak strain of 2006 (DRDE-06). Our results showed that Hsp90 is required at a very early stage of viral replication and Hsp90 inhibitor Geldanamycin (GA) can abrogate new virus particle formation more effectively in the case of S 27 than that of DRDE-06. Further analysis revealed that CHIKV nsP2 protein level is specifically reduced by GA treatment as well as HSP90-siRNA transfection; however, viral RNA remains unaltered. Immunoprecipitation analysis showed that nsP2 interacts with Hsp90 during infection; however this interaction is reduced in the presence of GA. In addition, our analysis on Hsp90 associated PI3K/Akt/mTOR signaling pathway demonstrated that CHIKV infection stabilizes Raf1 and activates Hsp90 client protein Akt, which in turn phosphorylates mTOR. Subsequently, this phosphorylation leads to the activation of two important downstream effectors, S6K and 4EBP1, which may facilitate translation of viral as well as cellular mRNAs. Hence, the data suggests that CHIKV infection is regulated by Hsp90 associated Akt phosphorylation and DRDE-06 is more efficient than S 27 in enhancing the activation of host signaling molecules for its efficient replication and virus production. CONCLUSION: Hsp90 positively regulates Chikungunya virus replication by stabilizing CHIKV-nsP2 through its interaction during infection. The study highlights the possible molecular mechanism of GA mediated inhibition of CHIKV replication and differential effect of this drug on S 27 and DRDE-06, which will be informative for developing effective anti-CHIKV therapies in future.
Mammalian non-classical major histocompatibility complex I and its receptors: Important contexts of gene, evolution, and immunity Soma Chattopadhyay, NtiyaG Chakraborty, Subhasis Chattopadhyay, BM Pratheek, TapasK Nayak, SubhransuS Sahoo, PrafullaK Mohanty Indian Journal of Human Genetics, 2014 The evolutionary conserved, less-polymorphic, nonclassical major histocompatibility complex (MHC) class I molecules: Qa-1 and its human homologue human leukocyte antigen-E (HLA-E) along with HLA-F, G and H cross-talk with the T-cell receptors and also interact with natural killer T-cells and other lymphocytes. Moreover, these nonclassical MHC molecules are known to interact with CD94/NKG2 heterodimeric receptors to induce immune responses and immune regulations. This dual role of Qa-1/HLA-E in terms of innate and adaptive immunity makes them more interesting. This review highlights the new updates of the mammalian nonclassical MHC-I molecules in terms of their gene organization, evolutionary perspective and their role in immunity.
Multi-organ single-cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases HWMB Sandra Lilja, Xinxiu Li, Martin Smelik, Eun Jung Lee, Joseph Loscalzo ... Cell Reports Medicine 4, 100956 , 2023 2023 Citations: 28
VIPER regulates naive T cell activation and effector responses: Implication in TLR4 associated acute stage T cell responses SS Sahoo, BM Pratheek, VS Meena, TK Nayak, PS Kumar, ... Scientific reports 8 (1), 7118 , 2018 2018 Citations: 14
High rates of co-infection of Dengue and Chikungunya virus in Odisha and Maharashtra, India during 2013 T Saswat, A Kumar, S Kumar, P Mamidi, S Muduli, NK Debata, NS Pal, ... Infection, Genetics and Evolution 35, 134-141 , 2015 2015 Citations: 90
Functional expression of TRPV channels in T cells and their implications in immune regulation RK Majhi, SS Sahoo, M Yadav, BM Pratheek, S Chattopadhyay, ... The FEBS journal 282 (14), 2661-2681 , 2015 2015 Citations: 158
In silico analysis of MHC-I restricted epitopes of Chikungunya virus proteins: Implication in understanding anti-CHIKV CD8+ T cell response and advancement of epitope based … BM Pratheek, AR Suryawanshi, S Chattopadhyay, S Chattopadhyay Infection, Genetics and Evolution 31, 118-126 , 2015 2015 Citations: 23
Regulation of Noxa-mediated apoptosis in Helicobacter pylori–infected gastric epithelial cells S Rath, L Das, SB Kokate, BM Pratheek, S Chattopadhyay, C Goswami, ... The FASEB Journal 29 (3), 796 , 2014 2014 Citations: 35
Induction of apoptosis by Fe (salen) Cl through caspase‐dependent pathway specifically in tumor cells N Pradhan, BM Pratheek, A Garai, A Kumar, VS Meena, S Ghosh, S Singh, ... Cell biology international 38 (10), 1118-1131 , 2014 2014 Citations: 14
Heat shock protein 90 positively regulates Chikungunya virus replication by stabilizing viral non-structural protein nsP2 during infection I Das, I Basantray, P Mamidi, TK Nayak, P BM, S Chattopadhyay, ... PloS one 9 (6), e100531 , 2014 2014 Citations: 85
Mammalian non-classical major histocompatibility complex I and its receptors: important contexts of gene, evolution, and immunity BM Pratheek, TK Nayak, SS Sahoo, PK Mohanty, S Chattopadhyay, ... Indian journal of human genetics 20 (2), 129 , 2014 2014 Citations: 24
Immune regulation and evasion of mammalian host cell immunity during viral infection BM Pratheek, S Saha, PK Maiti, S Chattopadhyay, S Chattopadhyay Indian Journal of Virology 24 (1), 1-15 , 2013 2013 Citations: 21
" Toll" Extending Its Gate from Drosophila Development to T Cell Response: Implication in Innate Immunity, Adaptive Immunity and Immunotherapy. S Chattopadhyay, S Pal, BM Pratheek, VS Meena, S Singh, PK Maiti Immunotherapy Insights , 2011 2011 Citations: 1
MOST CITED SCHOLAR PUBLICATIONS
Functional expression of TRPV channels in T cells and their implications in immune regulation RK Majhi, SS Sahoo, M Yadav, BM Pratheek, S Chattopadhyay, ... The FEBS journal 282 (14), 2661-2681 , 2015 2015 Citations: 158
High rates of co-infection of Dengue and Chikungunya virus in Odisha and Maharashtra, India during 2013 T Saswat, A Kumar, S Kumar, P Mamidi, S Muduli, NK Debata, NS Pal, ... Infection, Genetics and Evolution 35, 134-141 , 2015 2015 Citations: 90
Heat shock protein 90 positively regulates Chikungunya virus replication by stabilizing viral non-structural protein nsP2 during infection I Das, I Basantray, P Mamidi, TK Nayak, P BM, S Chattopadhyay, ... PloS one 9 (6), e100531 , 2014 2014 Citations: 85
Regulation of Noxa-mediated apoptosis in Helicobacter pylori–infected gastric epithelial cells S Rath, L Das, SB Kokate, BM Pratheek, S Chattopadhyay, C Goswami, ... The FASEB Journal 29 (3), 796 , 2014 2014 Citations: 35
Multi-organ single-cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases HWMB Sandra Lilja, Xinxiu Li, Martin Smelik, Eun Jung Lee, Joseph Loscalzo ... Cell Reports Medicine 4, 100956 , 2023 2023 Citations: 28
Mammalian non-classical major histocompatibility complex I and its receptors: important contexts of gene, evolution, and immunity BM Pratheek, TK Nayak, SS Sahoo, PK Mohanty, S Chattopadhyay, ... Indian journal of human genetics 20 (2), 129 , 2014 2014 Citations: 24
In silico analysis of MHC-I restricted epitopes of Chikungunya virus proteins: Implication in understanding anti-CHIKV CD8+ T cell response and advancement of epitope based … BM Pratheek, AR Suryawanshi, S Chattopadhyay, S Chattopadhyay Infection, Genetics and Evolution 31, 118-126 , 2015 2015 Citations: 23
Immune regulation and evasion of mammalian host cell immunity during viral infection BM Pratheek, S Saha, PK Maiti, S Chattopadhyay, S Chattopadhyay Indian Journal of Virology 24 (1), 1-15 , 2013 2013 Citations: 21
VIPER regulates naive T cell activation and effector responses: Implication in TLR4 associated acute stage T cell responses SS Sahoo, BM Pratheek, VS Meena, TK Nayak, PS Kumar, ... Scientific reports 8 (1), 7118 , 2018 2018 Citations: 14
Induction of apoptosis by Fe (salen) Cl through caspase‐dependent pathway specifically in tumor cells N Pradhan, BM Pratheek, A Garai, A Kumar, VS Meena, S Ghosh, S Singh, ... Cell biology international 38 (10), 1118-1131 , 2014 2014 Citations: 14
" Toll" Extending Its Gate from Drosophila Development to T Cell Response: Implication in Innate Immunity, Adaptive Immunity and Immunotherapy. S Chattopadhyay, S Pal, BM Pratheek, VS Meena, S Singh, PK Maiti Immunotherapy Insights , 2011 2011 Citations: 1
