Research Groups

Molecular Medicine: Cellular Immunology

Research Interests and Description

Group Leader: Dhiraj Kumar, PhD

Group Members

Research Interests

Host-Pathogen interactions in Mycobacterium tuberculosis infection, dynamic modeling in biological systems, design principles of biological networks.

Description of Research

Research focuses on understanding Host-Pathogen Interactions in case of Mycobacterium tuberculosis infection using high throughput experimentation and integrative (global) analytical approaches. We have been working on identification of host dependent survival axis for Mycobacterium tuberculosis. To that end we have identified several host factors through high-throughput siRNA screens in human and mouse cell line models. Interestingly, the host factors identified belong to the functional classes as diverse as metabolism to stress regulator and transcription factors. We were also able to identify, through the screens, modulation of autophagy - a crucial physiological process - as a key regulatory mechanism behind survival of M. tuberculosis inside the host cells. We aim to characterize in detail how host molecules known for their divergent physiological role converge as an autophagy regulator in the context of M. tuberculosis infection. Our long term goal is to evolve a dynamic model for the entire process of autophagy in the context of Mtb infection which can be simulated to obtain predictive results and validated through experiments.
We are also intrigued with the ability of the host cells to distinguish between a virulent and avirulent M. tuberculosis infection and thus display divergent cellular responses. Very early during the course of infection both the strains would probably be treated uniformly by the host, before the active subversion processes is established by the virulent strains leading to emergence of divergent responses. Through high density transcriptomic and proteomic analysis of human macrophages infected with H37Rv and H37Ra, we are currently trying to map the origin of divergent responses in the two cases. Our recent findings do indicate that an active subversion of host processes is elicited by a virulent M. tuberculosis strain. In a broader context, these strategies would complement each other in identifying and understanding most vulnerable host targets for killing intracellular M. tuberculosis.
Dynamic modeling of signaling events in biological systems and design principles of biological networks
Signaling events downstream to any cell surface receptor (such as TLRs, Cytokine receptors, Antigen receptors) or as a result of environmental variations/infections are complex processes often utilizing a select but overlapping set of molecules from the intracellular milieu, leading to a distinct cellular response. Cellular signaling machinery organized into a complex network is sufficient to modulate and execute most of the functions of the cell. Therefore, understanding how signaling machinery can distinguish and process the information in a context dependent manner becomes a complex and equally important issue in any physiological context.
Infection of host cells by Mtb perturbs cellular signaling machinery in a manner that allows Mtb to survive within the cell by successfully subverting the host bactericidal mechanisms. We are therefore, trying to establish how signaling events are perturbed upon Mtb infection that eventually determines cellular response. Due to the complex organization of the signaling network, we try to incorporate principles from graph theory and other dynamic or statistical modeling approaches to understand these processes. This also encourages us to look at generic organizational principles of biological network. We have recently identified such organizational principles in a cancer signaling network. Some of these might be applied to signaling machinery dedicated to any cellular processes.

Recent Publications

Karim, A.F., Chandra, P., Chopra, A., Siddiqui, Z., Bhaskar, A., Singh, A., Kumar, D. 2011. Express path analysis tyrosine kinase Src centric network regulating divergent host responses to Mycobacterium tuberculosis infection. J Biol Chem In press PubMed link

Chandra, N., Kumar, D., Rao, K. 2011. Systems biology of tuberculosis. Tuberculosis (Edinb) 5, 487-496

Kumar, D., Rao, K. 2010. Regulation between survival, persistence and elimination of intracellular mycobacteria: A nested equilibrium of delicate balances. Microbes Infect 13, 121-133 PubMed link

Fahey, M. E., Bennett, M.J., Mahon, C., Jaeger, S., Pache, L., Kumar, D., Shapiro, A., Rao, K., Chanda, S.K., Craik, C.S. 2011. GPS-prot: A web based visualization platform for integrating host-pathogen interaction data. BMC Bioinformatics 12, 298 PubMed link

Jayaswal, S., Kamal, M.A., Dua, R., Gupta, S., Majumdar, T., Das, G., Kumar, D., Rao, K.V.S. 2010. Identification of host-dependent survival factors for intracellular Mycobacterium tuberculosis through an siRNA screen. PLoS Pathogen 6, e1000839  PubMed link

Kumar, D., Nath, L., Kamal, M. A., Varshney, A., Jain, A., Singh, S., Rao, K.V. 2010. Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis. Cell 140, 731-743 PubMed link

ICGEB New Delhi

ICGEB Campus
Aruna Asaf Ali Marg
110 067 New Delhi
INDIA
Tel: +91-11-26741358/1007
Fax: +91-11-26742316
icgebicgeb.res.in

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