Malaria Liver-stage Biology, Key words: Parasite Knockout and Life cycle study, Antigen discovery, Malaria Vaccine, Drug discovery, Transcriptome, Protein-Protein interaction, Host-Parasite interaction, Genomics.
Summary of Research:
In the mammalian host, invasion of the hepatocytes is the first step towards developing malaria disease. Invasion by infective sporozoites is complex process and not understood very well. How parasite interacts with its host is the focus of my current research. We discovered that during early liver stage development a sporozoite surface protein (CSP) is introduced in the hepatocytes cytoplasm. CSP then shuttles into and out of nucleus of hepatocytes and changes the host transcription profile. CSP export into the cytoplasm of infected hepatocyte requires the presence of PEXEL / HTS motifs. The transport of CSP into the hepatocyte nucleus is then mediated by importins α3/β1 that binds to the nuclear localization signal (NLS) of CSP. The NLSs of CSP and NFκB p50 share the same importins. The entry of NFκB-p50 into the nucleus is strongly inhibited in cell lines expressing CSP, and in infected hepatocytes. Microarray data, from a N-terminal truncated CSP expressing cell line, showed that 40 NFκB targets were significantly down regulated. Presence of CSP in the host modifies thousands of host gene transcription that govern diverse biological processes such as metabolite transport, cell cycle, immune responses, cell growth, cell attachment, apoptosis and hypoxia and the overall effect is to enhance EEF growth.
We have the following two major areas of interest:
1. Understanding Host-parasite interactions during malaria liver stages development. Our focus is to identify Plasmodium proteins that modulate the hepatocyte cellular functions. Knockout of parasite genes combined with analyses of global changes (using omics techniques) in the infected host cell is used for the purpose.
2. Antigen/Drug discovery. We focus on
A] Knowledge based target identification for inhibitor design.
B] Known and novel compounds assay (ex vivo and in vivo) to test inhibitor/ drug efficacy.
C] Discovery of new antigens from liver-stage parasites and evaluation in animal models.
A multi-disciplinary approach is used to address above issues.
Pooja, Shreya, Zikra, Summaiya, Vimlesh, Hemant
• Ramalingaswami Fellow, DBT, India, 2009-2014
- Sharma, Neha; Kashif, Mohammad ; Singh, Vigyasa; Fontinha, Diana; Mukherjee, Budhaditya; Kumar, Dhruv ; Singh, Shailja; Prudêncio, Miguel; Singh, Agam# # Rathi, Brijesh# #(2021) Novel antiplasmodial compounds leveraged with multistage potency against human malaria parasite Plasmodium falciparum: In vitro, in vivo evaluations and pharmacokinetic studies. Journal of Medicinal Chemistry https://doi.org/10.1021/acs.jmedchem.1c00659
- Isha Pandey, Afshana Quadiri, Ishan Wadi, C.R. Pillai, Agam P. Singh# #, Ashis Das# #(2021) Conserved Plasmodium protein (PF3D7_0406000) of unknown function, in-silico analysis and cellular localization. Infection, Genetics and Evolution https://doi.org/10.1016/j.meegid.2021.104848
- Praveesh Valissery, Roshni Thapa, Jyoti Singh, Deepak Gaur, Jaydeep Bhattacharya# #, Agam Prasad Singh# #, Suman Kumar Dhar# #(2020) Potent in vivo antimalarial activity of water-soluble Artemisinin nano-preparations RSC Advances doi:10.1039/d0ra05597b
- Dabbu Kumar Jaijyan, Kavitha Govindasamy # #, Jyoti Singh, Shreya Bhattacharya, Agam Prasad Singh # # (2020) Establishment of a stable transfection method in Babesia microti and Identification of a novel bidirectional promoter of Babesia microti Scientific reports, doi:10.1038/s41598-020-72489-3
- Neha Sharma, Yash Gupta,, Meenakshi Bansal, Snigdha Singh, Prateek Pathak, Mohd Shahbaaz, Raman Mathur, Jyoti Singh, Mohammad Kashif, Maria Grishina, Vladimir Potemkin, Vinoth Rajendran, Poonam, Prakasha Kempaiah, Agam P Singh,# #, Brijesh Rathi # # (2020) Multistage Antiplasmodial Activity of Hydroxyethylamine Compounds, In vitro and In vivo Evaluations RSC Advances (2020), 10, 35516–35530 doi:10.1039/d0ra03997g
- Afshana Quadiri, Inderjeet Kalia, Mohammad Kashif, Agam Prasad Singh # # (2020) Identification and characterization of protective CD8+ T epitopes in a malaria vaccine candidate SLTRiP. Immunity, Inflammation and Disease [Wiley] DOI: 10.1002/iid3.283
- Sabyasachi Pradhan, Inderjeet Kalia, Sourav Singha Roy, Om P. Singh, Adak Tridibesh, Agam P. Singh # # & Suman K. Dhar # #(2019) Molecular characterization and expression profile of an alternate proliferating cell nuclear antigen homologue, PbPCNA2, in Plasmodium berghei. IUBMB Life doi: 10.1002/iub.2036
- Singh, Snigdha; Rajendran, Vinoth; Singh, Agam # #; Rathi, Brijesh# # et al (2018) Fast acting small molecules targeting malarial aspartyl-proteases, plasmepsins, inhibit malaria infection at multiple life stages. ACS Infectious diseases DOI: 10.1021/acsinfecdis.8b00197
- Jaijyan DK, Verma PK and Singh AP # # (2016) A novel FIKK kinase regulates the development of mosquito and liver stages of the malaria. Scientific Reports 6, 10.1038/srep39285
- Jaijyan DK, Singh H and Singh AP # # (2015) A Sporozoite and Liverstage Expressed Tryptophan Rich Protein Plays an Auxiliary Role in Plasmodium Liver Stage Development and is a Potential Vaccine Candidate. J. Biol. Chem., doi:10.1074/jbc.M114.588129
- Banerjee T, Jaijyan DK, Surolia N, Singh AP # #, Surolia A # # (2012). Apicoplast triose phosphate transporter (TPT) gene knockout is lethal for Plasmodium. Molecular & Biochemical Parasitology 186: 44-50.
- Singh AP # #, Zhang Y, No JH, Docampo R, Nussenzweig V, and Oldfield E # # (2010). Lipophilic Bisphosphonates are potent inhibitors of Plasmodium liver-stage growth. Antimicrobial Agents and Chemotherapy 54: 2987–2993.
- Singh AP # #, Buscaglia CA, Wang Q, Levay A, Nussenzweig DR, Walker JR, Winzeler EA, Hodaka Fujii H, Fontoura BMA and Nussenzweig V (2007). Plasmodium Circumsporozoite protein promotes the development of the Liver-stages of the parasite. Cell 131: 492-504.
- Singh AP, Ozwara H, Kocken CHM, Puri SK, Thomas AW and Chitnis C # # (2005). Targeted disruption of Plasmodium knowlesi Duffy binding protein confirms its role in junction formation during invasion. Molecular Microbiology 55:1925-34.
(# # denotes Corresponding author)
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