K. Natarajanprofessor, Director
Infectious Disease Immunology lab
In an effort to decipher the immune responses to mycobacteria, our group has been characterizing the interactions of M. tuberculosis with key players of the innate immune system including dendritic cells (DCs), macrophages and the effects thereof on regulating effector T cell responses. We have earlier demonstrated that many M. tuberculosis antigens strategically induce differentiation of DCs. However, functional characterization showed that these DCs induce suppressor responses to mycobacteria by downregulating the expression of pro-inflammatory cytokines and chemokines. This leads to poor recruitment and activation of antigen specific T cells leading to the induction of suppressor responses that benefits the pathogen. Further, we also demonstrated that the antigen differentiated DCs also serve as depots for mycobacterial multiplication and survival by downmodulating oxidative burst and interfering with the activation status of key intracellular signalling molecules. We demonstrated that conditioning antigen differentiated DCs with pro-inflammatory chemokines and cytokines leads to effective clearance of an established M. tuberculosis infection in vivo in mice. We also showed how differential triggering of protective and inhibitory receptors on DCs and macrophages govern cytokine responses during M. tuberculosis infection by induced expression and selective recruitment of SOCS1 to the receptors that lead to defective clearance of the pathogen from macrophages. In our recently study we demonstrated that M. tuberculosis indeed expresses antigens as a function of infection that employ different and yet complementary mechanisms to keep the immune responses suppressed thus contributing to long term establishment of infection. A key feature that regulated the above responses was calcium mobilization in infected cells. By deciphering calcium homeostasis in infected cells we have developed a new approach to treating multiple and extensively drug resistant M. tuberculosis infections in mice and guinea pigs. We have recently identified genes in the calcium-calmodulin and cysteine protease pathways that play a regulatory role in mediating immune responses and survival of M. tuberculosis inside dendritic cells.
We have recently initiated two new programs on deciphering host-pathogen interactions. One investigates the interactions of Streptococcus pneumoniae and M tuberculosis and their outcomes in immune priming. The other investigates the interactions of HIV with M tuberculosis.Ongoing Projects:
- 1. Regulation of Voltage Gated Calcium Channel function during Mycobacterium tuberculosis funded by DBT.
- 2. Deciphering macrophage functions during human immunodeficiency virus (HIV) and Mycobacterium tuberculosis co-infection
- 1. Singhal J., N Agrawal, M Vashishta, N G Priya, B K Tiwari, Y Singh, R Raman and K. Natarajan 2012. Suppression of dendritic cell mediated responses by genes in the calcium and cysteine protease pathways during Mycobacterium tuberculosis infection. J. Biol. Chem. 287: 11108-11121.
- 2. Srivastava, V, M Vashishta, S Gupta, R Singla, N Singla, D behera and K. Natarajan. 2011. Suppressors of cytokine signaling inhibit effector T cell responses during Mycobacterium tuberculosis infection Immunol. Cell Biol. 89: 786-791.
- 3. Gupta D, S Sharma, J Singhal, A T Satsangi, C Antony and K Natarajan. Suppression of TLR2 Induced Interleukin-12, Reactive Oxygen Species, Inducible Nitric Oxide Synthase Expression by Mycobacterium tuberculosis Antigens Expressed Inside Macrophages During the Course of Infection. J. Immunol 184: 5444-5454,2010.
- 4. Kumar, K., M. Tharad, S. Ganapathy, G. Ram, A. Narayan, J. A. Khan, R. Pratap, A. Ghosh, S. K. Samuchiwai, S. Kumar, K. Bhalla, D. Gupta, K. Natarajan, Y. Singh, A. Ranganathan. 2009. Phenylalanine-rich peptides potently bind ESAT6, a virulence determinant of Mycobacterium tuberculosis, and concurrently affect the pathogenís growth. PLoS One 10: e7615, 2009.
- 5. Srivastava V, M. Manchanda, S. Gupta, R. Singla, D. Behera, G. Das and K. Natarajan.TLR2 and DC-SIGNR1 differentially regulate Suppressors of Cytokine Signaling 1 in dendritic cells During Mycobacterium tuberculosis Infection. J. Biol. Chem. 284: 25532-25541,2009.
- 6. Singh M, P. Mukherjee, K. Narayanasamy, R. Arora, Somdutta, Shashank Gupta, K. Natarajan and P. Malhotra.. Proteome analysis of Plasmodium falciparum extracellular secretory antigens at asexual blood stages reveals a cohort of proteins with possible roles in immune modulation and signaling. Mol. Cell. Proteom. 8:2102-2118, 2009.
- 7. Gupta S, N Salam, V Srivastava, R Singla, D Behera, KU Khayyam, R Korde, P Malhotra, R Saxena and K Natarajan. Voltage Gated Calcium Channels Negatively Regulate Protective Immunity to Mycobacterium tuberculosis. PLoS One 4(4): e5305, 2009.
- 8. Salam, N., A. Gupta, S. Sharna, AS. Pahujani, A. Sinha, R. K. Saxena and K. Natarajan Protective immunity to Mycobacterium tuberculosis infection by chemokine and cytokine conditioned CFP10-differentiated dendritic cells. PLoS One 3(8): e2869, 2008.
- 9. Sinha A, A Singh, V Satchidanandam and K Natarajan. Impaired generation of reactive oxygen species during differentiation of Dendritic cells (DCs) by Mycobacterium tuberculosis secretory antigen (MTSA) and subsequent activation of MTSA-DCs by mycobacteria results in increased intracellular survival. J Immunol. 177: 468-478,2006.