Research Groups
Mammalian Biology: Immunology
Research Interests and Description
Group Leader: Kanury Venkata Subba Rao, MSc, PhDGroup Members
Research Interests
Lymphocyte activation, host-pathogen interactions, Mycobacterium tuberculosis, signal transduction, systems biologyDescription of Research
The Group is interested in understanding the regulatory parameters that influence the outcome of an immune response. One of the main areas of focus is to understand both the mechanisms controlling plasticity in receptor-initiated signaling pathways and how this pathway directs specific expression programs in lymphocytes. A second project concentrates on exploring the biology of host-pathogen interactions during infection with Mycobacterium tuberculosis (Mtb). Our larger goal here is to examine how the pathogen interferes with the functioning of the various components of the host, in order to ensure its survival.
With regards to receptor-mediated signaling in lymphocytes, we continue with our “systems-level” approach in order to understand how lymphocytes process and interpret signal in order to generate a context-specific cellular phenotypic response. To this end we are performing an analysis of the phospho-proteome in B cells, under conditions where various important signaling molecules are perturbed. The larger aim is to eventually generate a mathematical model that captures the plastic features of the signaling network, and define the mechanisms through which this network then directs the cellular response. Specific questions addressed as part of this study include signal processing by the MAP kinase pathway, and the role of the signaling network in controlling individual phases of the cell cycle. In addition to this we are also investigating the mechanism of Th1 versus Th2 differentiation of naïve human CD4 T cells.
In the context of host-pathogen interactions, our aim is to decipher the molecular mechanisms through which Mycobacterium tuberculosis successfully establishes a symbiotic relationship with the intracellular machinery of the host cell. To this end we are performing a genome-wide siRNA screen targeting human proteins in human macrophages infected with H37Rv. While the primary screen has been completed, validation of the initial hits is ongoing. These validated hits will then also be tested in cells infected with drug-resistant (including MDR) strains of Mtb. In conjunction with this, we also examining changes in the proteome of the host cell, following infection either with H37Rv, or MDR-Mtb. It is anticipated that the cumulative information provided by these experiments will help us to build dynamical networks, involving both host- and pathogen-derived molecules that describe the equilibration of the pathogen within the intracellular milieu of the host cell. The long-term goal is to eventually utilize such information for the development of novel therapeutic strategies.
We have recently initiated a program aimed at identifying biomarkers in samples from patients infected with active TB. The samples being evaluated are breath, serum, urine, and saliva. The proteome composition of serum, saliva, and urine are being analyzed using 2D-LC-MS/MS mass spectrometry, whereas volatile components of the breath are being examined by GC-MS.
Recent Publications
Kumar, D., Srikanth, R., Ahlfors, A., Lahesmaa, R., Rao, K.V.S. 2007. Capturing cell-fate decisions from the molecular signatures of a receptor-dependent signaling response. Mol. Systems Biol. 3, 150, 1-17Sharma, M., George, A.A., Singh, B.N., Sahoo, N.C., Rao, K.V.S. 2007. Regulation of Transcript Elongation through Cooperative and Ordered Recruitment of Cofactors. J. Biol. Chem. 282, 20887-20896
Basu, S.K., Kumar, D., Singh, D.K., Ganguly, N., Siddiqui, Z., Rao, K.V.S., Sharma, Pawan. 2006. Mycobacterium tuberculosis secreted antigen (MTSA-10) modulates macrophage function by redox regulation of phosphatases. FEBS J. 273, 5517-5534
George, A.A., Sharma, M., Singh, B.N., Sahoo, N.C., Rao, K.V.S. 2006. Transcription regulation from a TATA and INR-less promoter: Spatial segregation of core promoter function. EMBO J. 25, 811-821
Sethi, D.K., Agarwal, A., Manivel, V., Rao, K.V.S., Salunke, D.M. 2006. Differential epitope positioning within the germline antibody paratope enhances promiscuity in the primary response. Immunity 24, 429-438
Singh, D.K., Kumar, D., Siddiqui, Z., Basu, S.K., Kumar, V., Rao, K.V.S. 2005. The strength of receptor signaling is centrally controlled through a cooperative loop between Ca2+ and an oxidant signal. Cell 121, 281-293
