Infectious diseases: COVID-19, malaria, leishmaniasis, hepatitis C, HIV, and tuberculosis are ongoing pandemics worldwide, and looming multidrug-resistance mandates the development of new therapeutic and vaccine strategies. The scientific approaches of the past made significant progress; however, the intense focus was mostly on the individual genes and proteins, which seems insufficient to address these challenges. Instead, understanding the regulatory circuits and dynamic interactions between the biological components is required to address these challenges. We will employ a combination of immunology, systems biology, and chemical biology approaches to understand the complexity of the immune system and its perturbation in pathogenesis.
We are interested in understanding B cell fate decision to plasma cell and memory B cell in physiology and how pathogens perturb these fates. The mechanistic knowledge will direct us to design therapeutic strategies for B cell mediated disease and develop vaccination approaches to combat infectious diseases. We will implement iterative systems biology approaches involving contemporary omics and microscopy workflows to understand divergent B cells responses and cutting-edge chemical biology tools to design structure-function based vaccine antigens.
NFkB system in B cell fate decision
The efficacy of vaccination relies on at least two layers of defense. The first line of defense against reinfection is the pre-existing antibodies produced by plasma cells. The second line of defense is the rapid reactivation of memory lymphocytes. Activation of B cell is a critical step for the antibody production. Activated lymphocytes enter a proliferative phase, followed by differentiation to the effector cells and memory cells. We are accustomed to thinking about phenotypes as discrete states in which a single genotype maps to a distinct phenotype. However, single cell studies uncovered that each cell has a unique proteome implying that a single genotype can give rise to a range of phenotypes, with varying degrees of overlap(s). In support of this hypothesis, further experiments revealed a high degree of variability in the phenotypes of genetically identical cells grown and treated under identical conditions. Our study showed that the decision of a genetically identical B lymphocyte to enter the proliferative program is highly variable and NFkB system is a key regulator of B cell fate decision to plasma cell. Ongoing studies are trying to find out the role dynamics of NFkB in antibody homeostasis and memory B cell generation.
Quantitative understanding of lymphocytes response in infectious disease
Many infectious pathogens disseminate infection by exploiting the adaptive immune systems. Activation of lymphocyte B cell is critical step for adaptive immune response. Activated lymphocytes enter a proliferative phase followed by differentiation to the effector cells. The balance of proliferation and differentiation is critical for physiological lymphocyte dynamics whereas pathogenesis dysregulates the balance and leads to either aberrant proliferation or differentiation. Our research focus on quantitative understanding of the dynamics of B cell responses in infectious diseases in order to enable therapeutic development.
Structure-function guided development of peptide based immunomodulators
Peptide based therapeutic agents are advantageous over small molecules and large macromolecules because of its specificity, safety, low cost and easy handling. In laboratory, the synthesis, storage, cost and handling of peptide is much more user friendly than protein. Thus, for the last few decades, chemical biologist are trying to use peptides for multiple purposes, such as, vaccine candidates, a model system to study protein function and as a regulatory domain in artificial transcription factor. On this direction, we have designed a synthetic peptide based artificial transcription which can activate transcription in mammalian cell. On another context we have shown that a synthetic peptide based inhibitor of Fc receptor enhances antibody production in mouse model. Our research focus on developing peptides molecule with wide applications in various as aspects immunology.
Koushik Roy, PhD
M.Sc. 2006, Jadavpur University, India
Ph.D. 2014, CSIR-Indian Institute of Chemical Biology, India
Postdoc. 2021, University of California, Los Angeles, US
Koushik is originally from India. When Koushik was a master's student in Chemistry, he read Paul Ehlirch’s discoveries on chemotherapy and immunology. His obsession with chemical biology and immunology started after reading that article. He started his Ph.D. to understand biological systems at the molecular level and harness the knowledge to formulate chemotherapies in infectious diseases. He discovered cholesterol allosterically regulates MHC II function in disease leishmaniasis, and in another study, he engineered peptide-based vaccine antigen. He realized that the immunological system is very complex. The heterogeneity and dynamic nature of the immune systems aided the complexity of the immune systems. He did postdoc to understand the source of heterogeneity and the dynamic nature of antibody production. He developed a single-cell microscopic pipeline to map B cells' fate and discovered a new regulatory mechanism of plasma cell generation using a system biology approach. He started at the University of Utah as Assistant Professor, April 2021. He is interested to understand the regulatory mechanism of B cells’ fate to plasma cells and memory B cells and harness the knowledge to develop vaccination strategies in infectious diseases.
M.Sc. Biochemistry, Vidyasagar University, India
Pre-Med Student, Biology, University of Utah, Salt Lake City
BS-Biology, University of Utah, Salt Lake City
20. Purbey PK*, Roy K*, Gupta S and Paul MK, Mechanistic insight into the protective and pathogenic immune-responses against SARS-CoV-2, Molecular Immunology, 2023, 156, 111-126. (*Equal Contribution)
19. King J, Tran T, Paing M, Yin Y, Jaiswal A, Tso C, Roy K, Casero D, and Rao D. Regulation of T-independent B-cell responses by microRNA-146a. Frontier in Immunology, 2022, https://doi.org/10.3389/fimmu.2022.984302.
18. Roy K, Agarwal S, Banerjee R, Paul MK, Purbey PK, COVID-19, and gut immunomodulation. World J Gastroenterol 2021; 27(46): 7925-7942 (Review)
17. Roy K, Roy S and Roy S, A Mimotope Attached to an ITIM-SHP-1 Interaction Inhibitory Peptide Boosts Immune Response and Efficacy. RSC Medicinal Chemistry, 2021, 12(6):994-999.
16. Roy K*, Mitchell S*, Liu Y,Ohta S, Lin YS, Metzig M, Nutt S L and Hoffmann A. A regulatory circuit controlling the dynamics of NFkB cRel transitions B cells from proliferation to plasma cell differentiation. Immunity, 2019, 50(3):616-628. (* Equal Contribution)
15. Roy K,Shokhirev M, Mitchell S, Hoffmann A. Deriving quantitative cell biological information from dye-dilution lymphocyte proliferation experiments. Methods in Molecular Biology, 2018, 1707:81-94. (Book Chapter)
14. Mitchell S*,Roy K*, Zangle TA, Hoffmann A.Non-genetic origins of cell-to-cell variability in B-lymphocyte proliferation. Proceedings of the National Academy of Sciences, USA, 2018, Mar 20. 115(12):E2888-E2897. (*Equal contribution)
13. Roy K,Mazumder A, Ghosh P, Naiya G, Ghosh B, Roy S. A Peptide-based Synthetic Transcription Factor Selectively Activates Transcription in a Mammalian Cell. Chemical Communications, 2018, 54(13):1611-1614.
12. Roy K*,Mandloi S*, Chakrabarti S, Roy S. Cholesterol Corrects Altered Conformation of MHC-II Protein in Leishmania donovani Infected Macrophages: Implication in Therapy. PLOS Neglected Tropical Diseases, 2016 May 23;10(5):e0004710. (*Equal contribution)
11. Ghosh M*,Roy K*, Das Mukherjee D, Chakrabarti G, Roy Choudhury K, Roy S.Leishmania donovani infection enhances lateral mobility of macrophage membrane protein which is reversed by liposomal cholesterol. PLOS Neglected Tropical Diseases, 2014 Dec4;8(12):e3367. (*Equal contribution)
10. Dhar A, Mallick S, Ghosh P,MaitiA, Ahmed I, Bhattacharya S, Mandal T, Manna A, Roy K, Singh S, Nayak DK, Wilder PT, Markowitz J, Weber D, Ghosh MK, Chattopadhyay S, Guha R, Konar A, Bandyopadhyay S, Roy S. Simultaneous Inhibition of Key Growth Pathways in Melanoma Cells and Tumor Regression by a Designed Bidentate Constrained Helical Peptide. Biopolymers-Peptide Science, 2014 Apr; 101(4):344-58.
9. Roy K,Naskar K, Ghosh M, Roy S. Class II MHC/peptide interaction in Leishmania donovani infection: implications in vaccine design. Journal of Immunology, 2014, 192(12):5873-80.
8. Roy K, Ghosh M, Pal TK, Chakrabarti S, Roy S. Cholesterol lowering drug may influence cellular immune response by altering MHC II function.Journal of Lipid Research, 2013, 54(11):3106-15.
(F1000 Faculty: recommended)
7. Ghosh M, Roy K, Roy S. Immunomodulatory effects of antileishmanial drugs. Journal of Antimicrobial Chemotherapy, 2013, 68(12):2834-8.
6. Ghosh M, Solanki AK,Roy K,Dhoke RR, Ashish, Roy S. Carrier protein influences immunodominance hierarchy: implication in vaccine design. Vaccine, 2013, 31(41):4682-8.
5. Roy S, Ghosh P, Roy NS,Mazumder A, Roy K, Manna AK, Mallick S, Ahmed I. Peptide based Molecules as Protein-Protein Interaction Inhibitors: Tools for Chemical Genetics and Therapy. Current Chemical Biology, 2012, 6(2):145-163. (Review)
4. Mondal S,BardhanR, Mondal B, Dey A, Mukhopadhyay SS, Roy S, Guha R, Roy K. Synthesis, characterization and in vitro cytotoxicity assessment of hydroxyapatite from different bioresources for tissue engineering application. Bulletin of Material Science, 2012, 35(4), 683-691.
3. Mazumder A, Maiti A, Roy K, Roy S. A synthetic peptide mimic of λ-Cro shows sequence-specific binding in vitro and in vivo. ACS Chemical Biology, 2012, 15;7(6):1084-94.
2. Sen S,Roy K, Mukherjee S, Mukhopadhyay R, Roy S. Restoration of IFNγR subunit assembly, IFNγ signaling and parasite clearance in Leishmania donovani infected macrophages: role of membrane cholesterol. PLoS Pathogen, 2011, September 7(9), e1002229.
1. RahaP, Chattopadhyay S, Mukherjee S, Chattopadhyay R, Roy K, Roy S. Alternative sigma factors in the free state are equilibrium mixtures of open and compact conformations. Biochemistry, 2010, 49, 9809–9819.
- Rational thinking is essential.
- Feedback and criticism help to grow.
- Self-criticism improves self-awareness and personal growth.
- Diversity increases productivity.
- Mentorship should be part of the lab goals.
- Mental health is as important as physical health.
- Emotion is part of life.