Research Groups
Mammalian Biology: Immunology
Research Interests and Description
Research Interests
Lymphocyte activation, host-pathogen interactions, Mycobacterium tuberculosis, signal transduction, systems biology.
Description of Research
Both survival and long-term persistence of Mycobacterium tuberculosis (Mtb) within the host macrophage involves a dynamic equilibrium between competing processes initiated by the host cell at one end, and by the pathogen on the other. In response to infection, the host macrophage initiates a range of anti-microbial responses. These include the phagosome-lysozome fusion pathways, activation of the autophagic machinery, generation of reactive oxygen/nitrogen species, and induction of processes leading to cell apoptosis, among many others. On one level, therefore, survival of the intracellular Mtb depends upon its capacity to attenuate these host bactericidal pathways. In addition, the pathogen is also required to manipulate the metabolic machinery of the host cell, so as to ensure a nutrient rich environment that promotes its sustenance. Indeed it has been suggested that interactions between Mtb and the human macrophage involves cross-signaling mechanisms that permit homeostasis that conforms to Nash equilibria and, more specifically, to evolutionarily stable states.
Our primary focus is to understand the mechanisms by which Mtb adapts within the host macrophage as clearly important for developing new and more effective strategies for therapy. Given the many facets of these interactions, and the complexity inherent to each of these, we are combining experimental approaches with systems-level analyses of the network of interactions that are involved, and their dynamical modulation over time. The central aim is to capture the temporal dynamics of the process, where shifts in steady state can be defined in quantitative terms. We anticipate that such an approach may uncover new strategies for the treatment of TB infection. To achieve this larger goal, we are currently probing the diverse perturbations that the infecting pathogen induces in the host cell. This occurs either at the level of the lipidome, the metabolome, or the proteome. Mass spectrometry based approaches are being employed for this study and a key feature here is the examination of how each of these classes of molecules are modulated as a function of time.
In order to identify those hosts that determine survival of the pathogen inside macrophages, we recently performed a genome-wide siRNA screen against all known proteins in human macrophages infected with the virulent strain of M. tuberculosis, H37Rv. A subsequent screen against the identified host factors in cells infected with a panel of drug-resistant strains derived from diverse clades helped to shortlist a subset of host proteins that were critical for supporting survival of multiple drug-resistant strains of the pathogen. We have subsequently demonstrated, in proof-of-concept experiments, that targeting such host factors through small molecule inhibitors offers an effective way of eliminating both drug-sensitive and drug-resistant TB infections in the animal model. We are currently working with a pharmaceutical company to further build on these leads for drug development.
Recent Publications
Jailkhani, N., Ravichandran, S., Hegde, S.R., Siddiqui, Z., Mande, S.C., Rao, K.V.S. 2011. Delineation of key regulatory elements identifies points of vulnerability in the mitogen-activated signaling network. Genome Res In press PubMed link
Chaudhri, V.K., Kumar, D., Misra, M., Dua, R., Rao, K.V.S. 2010. Integration of a phosphatase cascade with the Mitogen Activated Protein Kinase pathway provides for a novel signal processing function. J Biol Chem 285, 1296-1310 PubMed link
Jayaswal, S., Kamal, Md. 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 Pathogens 6, e1000839 PubMed link
Kumar, D., Nath, L., Kamal, Md. A., Varshney, A., Jain, A., Singh, S., Rao, K.V.S. 2010. Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis. Cell 140, 731-743 PubMed link
Kumar, D., Srikanth, R., Ahlfors, H., Lahesmaa R., Rao, K.V.S. 2007. Capturing cell-fate decisions from the molecular signatures of a receptor-dependent signaling response. Mol Syst Biol 3, 150 PubMed link
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 PubMed link
